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QUINOLINE  DERIVATIVES  CONTAINING 

ARSENIC 


BY 

JOHN  RAVEN  JOHNSON 

B.  S.  University  of  Illinois,  1919 
M.  S.  University  of  Illinois,  1920 


THESIS 

SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS 
FOR  THE  DEGREE  OF  DOCTOR  OF  PHILOSOPHY  IN  CHEMISTRY 
IN  THE  GRADUATE  SCHOOL  OF  THE  UNIVERSITY 
OF  ILLINOIS,  1922. 


URBANA,  ILLINOIS 


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THE  GRADUATE  SCHOOL 


-May -9,  192-^. 


I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 

SUPERVISION  BY-  John  Haven  Johnson 

ENTITLED  "Quinoline  Derivatives  Containing  Arsenic^ " 


BE  ACCEPTED  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 
THE  DEGREE  OF  Dootor  of  Philosophy  in  Ghemistry_ 


Recommendation  concurred  in* 


i.') 


, 'p 


Committee 

on 

Final  Examination* 


*Required  for  doctor’s  degree  hut  not  for  master’s 


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TABLE  OF  CONTENTS 
Part  One. 

Quinoline  Derivatives  Containing  Arsenic 

I.  Introduction  1 

II.  Theoretical  Part  3 

A.  General  Resume  of  Methods  3 

B.  The  Bart  Reaction 7 

C.  The  Dobner  Cinchoninic  Acid  Synthesis  7 

III.  Experimental  Part  16 

A.  Preparation  of  Aryl  Ar sonic  Acids  IS 

B.  Condensation  of  Aminoaryl  Arsonic  Acids,  with 

Pyruvic  Acid  and  Aldehydes  27 

C.  Reactions  of  the  Condensation  Products  35 

IV.  Summary 42 

V.  Bibliography 43 

Part  Two. 

Benzyl  Arsonic  Acid 

I.  Introduction 45 

II.  Historical  Part  46 

III.  Theoretical  Part  48 

IV.  Experimental  Part  54 

V.  Summary 66 

VI.  Bibliography 67 

Vita 63 


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Digitized  by  the  Internet  Archive 

in  2015 


https://archive.org/details/quinolinederivatOOjohn 


1 

I.  INTRODUCTION 

This  investigation  was  undertaken  with  the  object  of 
studying  new  organic  derivatives  of  arsenic  which  might  possess 
valuable  therapeutic  properties,  and  to  develop  a substance  which 
would  be  superior  to  Arsphenamine*  in  the  treatment  of  diseases 
caused  by  trypanosomes  and  spirochetes. 

This  field  of  chemotherapy  was  opened  up  by  Ehrlich 
and  Bertheim  in  1907,  and  several  years  later  they  developed 
Salvarsan  and  Neosalvarsan,  two  substances  which  have  proved  to 
bo  very  valuable  therapeutic  materials.  Since  the  development  of 
these  substances  several  hundred  new  organic  arsenic  compounds 
have  been  prepared,  but  none  has  displaced  Salvarsan  and  Neosal- 
, varsan.  Recent  clinical  work  has  given  evidence  that  these  sub- 
' stances  are  far  from  ideal,  and  it  is  well  known  that  the  advanced 
stages  of  syphilis  cannot  be  cured  by  the  application  of  these 
materials, 

previous  observation  has  shown  that  in  order  to 
possess  trypanocidal  action  the  organic  arsenical  must  contain 
nitrogen  in  some  form;  further,  that  nitrogen  atoms  covered  by 
certain  organic  radicals  are  more  active  than  free  amino  groups, 
and  that  the  substances  are  in  general  more  stable,  and  conse- 
quently less  toxic. 

From  these  considerations  it  was  decided  to  take  up 

the  preparation  of  arsenicals  containing  tertiary  nitrogen  in  a 

ring  .system,  particularly  in  the  quinoline  grouping.  This  nucleus 

is  present  in  many  of  the  common  alkaloids  and  in  other  substances 
» 

The  official  Anerican  Name  for  "Salvarsan". 

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which  arc  physiologically  active. 

The  preparation  of  quinoline  derivatives  containing 
arsenic  was  the  subject  of  a paper  by  Frlnkel^  and  LO'wy  in  1913, 
and  these  investigators  applied  many  general  reactions  without 
success.  They  were  able,  however,  by  applying  the  D5bner-Liiller 
quinaldine  synthesis,  to  obtain  small  quantities  of  a substance 
which  they  formulated  as  quinaldine-6-arsonic  acid.  By  reduction 
with  sodium  amalgam  they  obtained  a substance  which  corresponded 
to  quinaldine -S-s-rsenious  oxide.  These  substances  were  obtained 
in  such  small  quantities  that  the  authors  were  unable  to  make  a 
thorough  investigation  of  them,  and  it  appears  uncertain  that  they 
were  re^ ly  quinaldine  arsenic  derivatives. 

Since  the  quinaldine  synthesis  mentioned  yielded  an 
arsenic  containing  product,  it  seemed  worth  while  to  investigate 
the  closely  related  Ddbner  cinchoninic  acid  synthesis  with  the  idea 
of  preparing  cinchoninic  acid  derivatives  containing  arsenic. 


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II.  THEORETICAL  PART 

In  considering  the  33mthesis  of  quinoline  derivatives 
containing  arsenic  there  appeared  to  be  two  ways  of  attacking  the  j 

I 

problem:  the  direct  method,  starting  with  a quinoline  nucleus  al-  | 
ready  formed  and  introducing  arsenic  into  the  molecule,  and  the  | 
indirect  method,  building  a quinoline  ring  into  a molecule  al- 
ready containing  arsenic. 


for  the  introduction  of  arsenic  into  the  quinoline  molecule.  Of 
these  the  follov/ing  were  considered: 

The  Be champ  Reaction:  This  has  proved  valuable  for  the  arsenation 
of  aryl  amines,  and  of  indole®  derivatives: 


Frenkel’’  and  Ldwy  applied  this  method  to  quinoline,  and  tetra- 
hydroquinoline,  but  were  •'unable  to  obtain  the  desired  arsenic 
acids  even  on  heating  to  300°  under  pressure. 

Direct  Arsenation  with  Arsenic  Chloride:  This  had  led  to  a number 
of  p-alkylaminophenyl  arsenious  chlorides  from  the  corresponding 
mono  and  dialkylanilines  and  arsenic  chloride^ 


By  the  treatment  of  quinoline,  8-hydroxy  quinoline,  and  tetrahydro- 
quinoline  with  arsenic  chloride,  Frankel  and  Ldwy  obtained  addition 
compounds  which  on  treatment  ’^rith  water  liberated  arsenic  tri- 


A . General  Re sum/  of  Methods 
There  are  a number  of  ways  which  were  deemed  applicable 


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oxide;  the  arsenic  chloride  could  not  be  introduced  into  the  ring 
by  treatment  of  the  addition  compounds  '.iritn  aluminum  chloride. 


Interaction  of  Arsenic  chloride,  an  aryl  halide  and  metallic 
sodium:  This  reaction  was  used  by  Michaelia**  for  the  synthesis  of 
a large  number  of  arsenic  compounds,  but  the  reaction  does  not  run 
smoothly  and  is  only  used  at  the  present  time  in  a few  instances. 


The  Bart  Reaction^;  An  aryl  amino  group  is  replaced  by  the  arsenic  ! 
acid  grouping  through  the  diazo  compound,  by  treating  with  sodium  i 
arsenite:  i 


The  Meyer  Reaction^:  The  treatment  of  alkyl  halides  with  sodium 
arsenite  proved  to  be  a valuable  means  of  obtaining  aliphatic 
arsonic  acids.  Since  halogens  in  the  3-  and  4-positions  in  the 
quinoline  ring  are  aliphatic  in  character,  it  might  be  possible  to 
apply  the  Meyer  reaction.  Certainly  compounds  of  the  type  (b) 


would  be  expected  to  react  with  sodium  arsenite  to  give  quinolyl 
methyl  arsonic  acids. 


Indirect  Syntheses. 

In  the  literature  is  reported  a large  number  of  syn- 
theses of  quinoline  and  its  derivatives  in  which  the  pyridin 


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ring  is  closed  onto  a oenzene  nucleus.  Of  tjiese  the  following 
were  considered  to  be  of  possible  application  to  compounds  con- 
taining arsenic. 

Skraup*  8 synthesis'^;  The  treatment  of  an  aromatic  amine  with  gly- 
cerol, sulfuric  acid  and  an  oxidizing  agent  has  given  a large 
number  of  quinoline  derivatives,  and  the  reaction  has  proved  to 
be  quite  general.  If  p-arsanilic  acid  were  used  in  this  reaction 
it  would  be  expected  that  quinoline-6-arsonic  acid  would  result, 
but  it  was  found  by  Frenkel  and  L6wy  that  the  arsenic  was  split 
off  and  only  quinoline  resulted^ 

Knorr*  s synthesis^  from  aniline  and  acetoacetic  ester: 

GHa 

GH3COGH2CO2R 


thru  the 
a n i f r ct  e 


X*OH 


This  reaction  was  applied  to  arsanilic  acid  and  did  not  give  the 

1 

desired  product. 


Kulisch* 3 synthesis^  from  o-toluidine  and  glyoxal: 


GHa  0=GH  , . 

* I St  r o o 

lffi,0=CH 


+ 3HjO 
35  - yields. 


The  D^bner-Miller  qulnaldine  synthesis^?  This  reaction  was  used 
by  FrSnkel  and  Ldwy  and  they  obtained  a product  which  they  stated 
to  be  quinaldine-6-ar sonic  acid.  It  i 

s 


A repition  of  thi 


,s  rather  surprising,  how- 

s reaction  gave  large  quantities  of 
quinoline, but  the  formation  of  a crystalline  pierate, decom- 
posing from  266-275®, led  to  the  belief  that  some  qulnollne- 

6-areonlc  acid  was  present  In  the  reaction  mixture  altho  It 
could  not  be  isolated  as  ouchi. 


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ever,  that  their  product  was  insoluble  in  alkalies  and  in  acids, 
and  from  analogy  one  would  expect  the  compound  mentioned  to  be 
soluble  in  both  of  these  reagents. 


®3 

On  reduction  with  sodium  amalgam  they  obtained  a compound  soluble 
in  alkalies  which  they  stated  to  be  the  corresponding  arsenious 
oxide. 


and  H B r 


'“•“CD 


Ddbner* 3 cinohoninic  acid  synthesis^^  This  reaction  is  of  general 


application  and  is  taken  up  in  detail  later. 

CHaCOCOOH 


C0.H 


I 


UHp  OGHR 


Frledlander* 3 synthesis^ ^ and  its  extensions:  Although  the  syn- 
thesis of  quinoline  derivatives  from  o-aminobenzaldehyde  itself 


Solution 


CHO 


H^C-R 


OC-R’  alkali 

13  14  ^ Dr 

is  not  practical,  certain  extensions  'nave  proved  to  be  quite 

valuable  means  of  S3mthesizing  quinoline  derivatives; 

00^ 

CHq 

GO-C6H4R 


I s a t In 


GO-GQ3H 


h. 


GHgGeH4R 
GOgH 


CeH^R 


GgH^R 


.3& 


Since  this  work  was  started,  two  substances  of  the  types  (a)  and 
4® 

(b)  have  been  prepared  ’ivith  the  ar sonic  acid  grouping  in  the  p- 


position.  It  seems  likely  that  cinchoninic  acid  derivatives  could 


A; 


IF 


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7 


readily  be  prepared  from  these  substances  by  application  of  the 
above  reactions. 

After  a consideration  of  the  aoove  reactions  and  the 
possibilities  offered,  it  appeared  that  the  ir.ost  promising  methods 
of  obtaining  quinoline  derivatives  containing  arsenic  V7ere  the 
Bart  reaction  and  the  Dflbner  cinchonic  acid  synthesis. 

B,  The  Bart  Reaction 

For  trying  this  reaction  6 -amino quinoline  was  diazo- 
tized  and  treated  with  sodium  arsenite  according  to  the  usual 
procedure.  Although  an  evolution  of  nitrogen  occurred  on  mixing 
the  diazo-  and  arsenite  solutions,  no  quinoline  arsonic  acid  could 
be  isolated  from  the  material.  Since  the  Bart  reaction  has  proved 
to  be  quite  general  for  all  substituted  types  of  aromatic  amines 
it  seemed  unusual  that  the  quinoline  arsonic  acid  was  not  obtained 
by  this  method.  It  is  noted,  however,  i5hat  Schmidt'^  used  o-  and 
p-aminodiphenyl  and  obtained  tarry  browai  substances  from  which  the 
arsonic  acids  could  not  be  isolated. 

C,  The  Dflbner  Cinchoninic  Acid  Synthesis. 

The  condensation  of  aromatic  amines  with  pyruvic  acid 
and  aldehydes  in  alcoholic  solution  has  led  to  the  production  of 
a large  number  of  2-substituted  quinoline-4-carboxylic  acids. 

This  reaction  has  been  found  to  be  quite  general  for  aryl  amines 
and  almost  unlimited  in  its  applications.  The  following  examples 
indicate  the  many  types  of  aromatic  amines  which  have  been  con- 
verted into  the  corresponding  cinchoninic  acids:  the  toluidines, 
aminophenols  and  their  ethers,  anthranilic  acid,  m-  and  p-halo- 

I 


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genated  anilines^®,  m-  and  p-aminoacet ophenone^® , p-aminoacet- 
anilide'®,  benzidine'®,  and  the  naphthyl  amines.  The  reaction 

seems  to  be  even  more  general  for  aldehydes  than  amines,  since 
both  aromatic  and  aliphatic  aldehydes,  incl'jding  formaldehyde  and 
furfural,  will  give  cinchoninic  acids. 

In  a number  of  cases  the  yields  in  this  condensation 
are  unsatisfactory,  and  this  is  due  to  the  formation  of  hydrogen- 
ated by-products  and  a group  of  alkali  insoluble  substances.  The 
nature  of  the  latter  was  investigated  by  Dobner",  and  by  Garza- 
rolli-Thurnlackh’''’^,  who  assigned  to  them  the  formula  of  the  anil 
of  a diketopyrrolidine  derivative: 

,G0-G=1T 


N. 


GH-GHs 


GgHg 

D6bner' 3 "anil"  compa’nd,  m.p.  335®. 

It  was  noted  that  the  solvent  plays  an  important  part  in  determin- 
ing the  course  of  the  condensation.  Alcohol  favors  cinchoninic 
acid  formation,  whereas  ether  and  benzene  lead  almost  exclusively 
to  the  anils  of  diketopyrrolidines.  It  was  also  found  that  the 
substitution  of  esters  of  pyruvic  acid  led  to  the  diketopyrroli- 
dine anil. 

The  most  coiTiprehensi ve  study  of  the  limitations  of  this 
reaction  was  made  by  Borsche  who  studied  the  effect  of  substitu- 
ents in  all  three  of  the  reactants.  The  results  of  this  and 

previous  investigations  may  be  stated  briefly  as  follov/s: 

i.  The  introduction  of  methyl  or  hydroxy  groups  into 
the  m-position  in  the  aryl  amines  increased  the  yield  of  cinchon- 
inic acid,  due  to  its  activating  effect  on  the  hydrogen  in  the 
o-position  to  the  amino  group.  This  §LCtivating  effect  seemed  to 


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( 


9 


"be  at  a maximum  in  ^-naphthyl amine,  from  which  no  cLiketopyrroli- 
dine  derivative  could  he  obtained  even  when  ether  was  used  as  the 
solvent.  The  reaction  with  the  nit roanilines  went  exclusively  to 
the  diketopyrrolidines,  and  from  these  atriines  no  cinchoninio  acids 
could  be  obtained  under  the  most  favorable  circumstances. 

ii.  The  reaction  is  a general  one  for  aldehydes,  and 
with  the  use  of  ^-naphthyl amine  especially,  cinchoninio  acids  can 
be  obtained  from  all  aldehydes.  This  reaction  had  previously  been 
proposed  by  D5bnsr*°  as  a specific  reaction  for  all  aldehydes. 

iii.  The  introduction  of  phenyl,  o-nitrophenyl  and 
benzoyl  groups  into  the  pyruvic  acid  molecule  caused  the  reaction 
to  run  chiefly  to  diketopyrrolidine  derivatives  in  the  case  of  the 
simple  aryl  amines.  With  -naphthylamine,  however,  the  usual  cin- 
choninic  acids  were  formed.  The  introduction  of  the  benzyl  group 
into  the  pyruvic  acid  rest  led  to  the  usual  mixture  of  both  sub- 
stances, but  the  diketopyrrolidine  derivative  predominates  in  the 
case  of  the  simple  aryl  amines. 

When  arsanilic  acid,  benzaldehyde,  and  pyruvic  acid  are 
heated  together  in  absolute  alcoholic  solution,  a condensation 
product  is  obtained  in  good  yields.  The  composition  of  this  su'o- 
stance  corresponds  to  that  of  a cinchoninio  acid,  I,  or  a simple 
diketopyrrolidine  derivative,  II: 


HgOgAS 


I. 


cp^ 


GO-CO 


CH-OH, 


^ ^ II*  GgHs 

CieHisOshAe  Ci6Hi405NAe 

The  usual  separation  of  these  substances  by  the  solution  of  the 


:■-  n’P  lerv  u*?ri-:*f-*  ^nrYr^  tettm&tko  6ntt 

‘ .^  .V 

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% 

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I i. 


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cinchoninic  acid  in  alkalies  cannot  be  applied  since  an  alkali 
soluble  group  is  already  present  in  the  molecule.  In  order  to 
determine  the  structure  of  the  substance  a study  was  made  of  its 
reactions. 

The  condensation  product  is  unstable  toward  hot  mineral 
acids,  and  therefore  the  usual  reaction  of  replacing  the  arsenic 
acid  group  by  iodine,  and  identification  of  the  resulting  iodo-com- 
pound  cannot  be  applied.  It  was  found  ttat  the  compound  gave  off 
approximately  one  mole  of  carbon  dioxide  on  heating  to  its  decom- 
position point.  This  was  considered  to  be  evidence  for  the  cin- 
choninic acid  structure  since  it  is  well  kno’^  that  these  substance 
readily  loss  one  mole  of  carbon  dioxide  on  heating  above  their 
melting  points. 

It  was  thought  likely  that  a fusion  of  the  substance 
with  sodium  hydroxide  would  give  additional  evidence,  since  the 
2-phenylquinoline-4-carboxylic  acid-6 -ar sonic  acid,  I,  would  be^ 
expected  to  give  either  3-phenyl  quinoline  or  2-phenyl  6 -hydroxy 
quinoline  under  this  treatment.  It  was  found,  however,  that  the 
chief  nitrogenous  product  from  the  alkaline  fusion  was  aniline. 

This  could  hardly  be  explained  on  the  cinchoninic  acid  formula, 
and  the  formation  of  carbon  dioxide  is  difficult  to  explain  on 
the  diketopyrrolidine  formula.  It  was  therefor e decided  to  pre- 
pare a diketopyrrolidine  derivative  and  determine  whether  it  gave 

carbon  dioxide  on  heating. 

For  this  purpose  the  simple  diketopyrrolidine.  III, 
prepared  from  p-nit raniline  was  used,  and  it  was  found  that  on 


'"i  - . 


5 . ’ I 


• I 


I ^ 


ii  -r, 

.'w  <-4’.  » r;iri,£  ifXve  LrAv 

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9 


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‘«i 


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^ " T '»r^” 

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ir. :'  -»-.  ifi'  . 5/tc4v2^ji»-*t3>x;XiF  ':Rihi.- 

''.’-:'u  ■’•  “ 

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' , ‘ ■’^1  y 

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. ‘t  .I'ty'pi.  .:e:z  i^y .i  c-^yI'^^P  J 

' , ■■  ,.'i 

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-■  . ' i' 


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11 


NO 


GSaGOGOOH 


•m. 


alcoholic 

GgH^GHO 


NO, 


N' 


/ 


GO-GO 


III. 


heating  this  substance  in  boiling  ethyl  benzoate  for  fifteen 
minutes  63^  of  one  mole  of  carbon  dioxide  was  evolved.  To 
determine  the  effect  of  the  arsenic  acid  grouping  a sample  was 
mixed  with  nitrophenyl  arsenic  acid  and  heated  in  boiling  ethyl 
benzoate  under  the  same  conditions.  In  this  case  the  amount  of 
carbon  dioxide  amounted  to  95‘fo  of  one  mole. 

These  results,  together  with  the  behavior  on  alkaline 
fusion,  indicate  that  the  first  conclusion  was  incorrect,  and 
that  the  compound  is  not  a quinoline  arsonic  acid.  This  conclu- 
sion is  supported  by  the  fact  that  the  same  condensation  product 
is  obtained  when  the  reaction  is  carried  out  in  ethereal  suspen- 
sion, and  also  when  the  ethyl  ester  of  pyruvic  acid  is  substi- 
tuted for  the  free  acid.  In  both  of  these  cases  the  diketopyrroli- 
dine  derivatives  would  be  expected,  and  the  product  proved  to  be 
identical  with  the  original  condensation  product. 

Since  the  evidence  for  the  di ketopyrrolidine  is  based 
only  on  the  analogy  to  p-nit raniline,  it  seemed  advisable  to  con- 
duct further  experiments.  It  would  be  expected  that  the  4-keto 
group  would  easily  form  an  anil  with  an  aromatic  amine,  leading 
to  compounds  of  the  type  IV,  containing  the  arsonic  acid  grouping: 


R 

IV. 


N. 


/GO-G=N 


GH-GHs 

CsHb 


t 


;1 


i 


-V 


1 , 


' •i 


n 


ii 


I j 


\ 


1 


.V  - 5 ii  AtflJCi'  A 

■rfS 


t ‘c: 


} . 


’.  ’-J! 


•f.  - 


■\)<  ' ,» 


, 1 


^•■S<'‘'-<  - ■ ^ 

. •<.  ; . jK:  ' - • ^t-  d - <?■ ! ,'S''  i t- 

; -r  f>'zr 

V ^ . ' ;=•»  . i ' 

t ■ «:,  *-dt?  iSt  •i.vr:'- 

• ^ '■  i . .^'  ■ '3  '■ 

- ' **  , 

i-  j:»-  ■■"  J ‘ i vi^ii^'  1'  ft  h - 


■i 


p ■■<'■  X" 

' . t\Tt  t ’.i  .'.;S 


i'd» 

A 


s 


,:S:v 


■ f 


* 21 


hi 


\ : ■ ■"'  . ;-'n-c.  .ih?- 


■• ; I tr  i .f'i .'  iti  :■;  i 


V;1 


"“31  ‘...  iL 


1 


'.  If 


,'  I 


S - 


• 'I 


>#i  *j 


fir  :5;s=  V"^:S:fi’ia'’ 


o.'xarasq^s^-jJ, ! 


is 

One  would  expect  this  reaction  to  take  place  very  readily,  since 
compounds  of  the  type  IV  are  usually  formed  as  by-products  when 
the  DSbnor  cinchoninic  acid  synthesis  is  carried  out. 

In  order  to  prepare  this  anil  the  condensation  product 
was  dissolved  in  boiling  alcohol  and  treated  with  one  mole  of 
aniline.  From  the  reaction  mixture  a product  was  obtained  which 
was  insoluble  in  boiling  ISfJo  sodium  hydroxide  and  melted  from 
147®-! 48®.  The  insolubility  in  sodium  hydroxide  indicated  that 
the  substance  no  longer  contained  the  arsonic  acid  grouping  and 
could  not  be  the  desired  anil, 

A review  was  made  of  the  literature  on  the  addition  of 
pyruvic  acid  to  benzylidene  aniline,  and  it  was  noted  that  Schiff^^ 
had  carried  out  the  reaction  in  benzene  solution.  In  this  way  he 
obtained  a compound  melting  at  147®,  which  he  gave  the  formula: 

,G0-C0 

< I 

ch-ch, 

CsHs 

and  it  seemed  possible  that  the  alkali  insoluble  substance  men- 
tioned aoove  was  identical  with  Schiff ' s confound. 

1 7 

Garzarolli-Thurnlackh  on  repeating  the  work  of 
Schiff,  obtained  the  compound  m.p.  147®-148^,  along  with  larger 
quantities  of  Ddbner' s anil  compound,  m.p.  225®.  It  seemed  likely, 
therefore,  that  by  using  an  excess  of  aniline  the  D5bner  anil  com- 
pound could  be  obtained  from  the  arsanilic  acid  condensation 
product.  The  latter  was  treated  with  two  and  one  half  moles  of 
aniline  and  gave  arsanilic  acid,  but  none  of  the  anil  could  be 
isolated. 

The  behavior  of  the  condensation  product  on  treatment 


C6HsH*GH-06Hs  +GH3COGO3H 


, V i. \ ^ tvo^X-i  .•frft  V:i‘rJ  ^ ^ 'X :- - 


«rtO 


™ .fv.».  L*  W/ io’^X/u?o<|B>c^ 

. ..  ^ ire:  «r.f*l*-tl-SH:iiJ 

( 


,:r  i)df  p1cl¥  <i’-u'>^i?T^-'';‘4..'Vei;^0  iil  <"' 


- T U'4  V. 


. f : o rc;2;bos-  ■ ^a'  .'iUmI  aoJ-^o*eT  e^Sif  .mltlpJ' 

“ • * . . - fc  . - 


•.  . -£ii 5 ’01  jiniliccf  v ^>Z(^;/xSaai  «?''» 

jf  ■ * "'  \4 

i-r:  i ? V i f-  -:  • u/  i -• . ? -*!f  t s^i  - fli  T • ^ 8*’ 

iiin 


■ . . . X 

.:■’  v: 


-■  f 


A.  - 


, Jt.  ij  i . ->•• 

' ■■■  * ";-i'  - nr^  - r-u*" 


•*  V.  V4v'.*:':'  X..  ^;v*  No  i;>.-/'^>  »f,V.  ’vf|' 


-••  - - - •!,  T - ■ » '''*'1 


' '•  ri^-7  •■> 


V ■'  ' .5 

1 , /'  '^' w 

c.--'  • 'Iv'^  i)  i ;j<lI  v?^’ .eiiijPV'r^--:?  ''i#A^ 

'cf'> 


.1  --  -I  #'.<( 


./  . 


N 


; 


r;  u*.- 

:,  n 4‘V-I?  .4.:  /;.:>,  /,  f 2 umji  .0£ff  * j 


1.^' 


^ ^ -.t  ;,v' ..  ' ; .'  i;:':cfe  r, tV -■  XX'  Cj  * 

v: 


r-is 


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»T 


*■ 


*1  ■ -5J  '--s  - 


bfit/o^OD 

'-'  *'*461  ' " - "^i. 

^.. 'i-'i  XA/'  ‘;.o  .Jin 


H'r 


'5^ 

' -« 


fo,:  Ji;a‘ro*.,->o  .-..-i'.'  'jU2V'-m  ft-i;  -atil  Kitted 


S»J 


u/'Jioi;;  Yi-  ’ * V yr:B’c^  iU  5| 

^ ' ■'■■'■■'  "I.  . V ' jVjlEr,1 


• J 'iluoo Nii,  •*’  \o--f(fi.oa  'tini  ^-fiic^. , '-rf^ 


• ■'J»  Y\.. 


■ ■ ■ ■ ■ 


i:  ViXr  -t' 


T 


kv 


k'  ■ 


1 3 


with  sodium  hydroxide  is  worthy  of  mention.  The  material  dis- 
solves readily  in  one  mole  of  aqueous  sodium  hydroxide  to  a cl 
yellow  solution,  which  on  standing  at  room  temperature  deposits  a 
white  precipitate.  The  solution  has  a strong  odor  of  benzaldehyde, 
and  is  acid  in  reaction  to  litmus  paper.  The  precipitate  contains 

arsenic  and  is  soluble  in  alkalies;  it  is  very  difficult  to  purify 

0 o 

and  the  impure  material  melted  with  decomposition  from  140  -150  . 
With  two  or  more  moles  of  alkali  the  condensation  product  dissolves 
to  a clear  yellow  solution  which  does  not  become  turbid  or  deposit 
any  precipitate. 


explained  on  the  basis  of  the  diketopyrrolidine  formula,  II,  a 
consideration  was  mads  of  other  isomers  and  the  following  was 
suggested,  formula  V: 


Although  no  compounds  of  this  structure  are  described  in  the 
literature,  it  was  noticed  that  a compound  of  this  type  was  sug- 
gested as  a hypothetical  intermediate  in  the  formation  of  D6bner' s 


Since  the  reactions  enumerated  could  not  be  adequately 


V. 


T7 

anil  compound  according  to  the  following  mechanism 


B 


GHgCH-OH 


HaC-Ca 


' ’ Wi 


‘."f 


^ ’ ^Wr . 

-v^rrrrzu-.  • ' ~ -rjaCTiS': .‘ ' ~ .64ars.*^~ia;!^^  atr 


T'-; 


■.-  ^1 


[M 


* * ' ■», 


.1  e.rlT  . f-tf* 


..  V.  C' ' d.  l/'.'v':i  tf  f^t'  li  ?Jf'^ 


ir , ^-u- 


I 


:.r  l •' r -t  «v  -^’OXicv 

• ' ► / • ‘ 

.•  . ‘’^*ji;.  •■••:«•>  ,'X  ;rHX..:aA-i>  ai  o-iiwitw  . 


L- 


L'.  I 


. et'lc«  n^xW 


1 


V-  I ^ ^ 


, .a  fi  ’-•  Oi  i“  CXiU  Irv-  i ^i-'i  V : ■•  i 


,j.'  Ct» . ••C-- i »‘v  ■'•■JO 


> »?'  1 Ji  J.  'i'  v: 

■^.‘V 


<i 

M 


o> 


: X :.^  *»•  ••  -.?-vy . JN  ♦•  . .•:  ..•  ii’*'ii? 


•i  t 


'.«}•.  .B  ". 


V:K.  ‘.’l 


*■ 


• 1' 


■*"  '•  'iliV'i. 


s 


'r  hr..ff  '.;;■  cT??  K .>'.‘^*,  Tv 

' ■ I.  ' ‘b  ’ ^ 


iT^ 


r ts'  7 'lo  xj? vi;{'’7Q’d  j ^o*i'  ■ if  iX  f|^ 

' ' ' . ' . .. ' ^”  ' ■ . , . ..  f '/ 

*v‘  « cueyfcs?^'^’ 


I - 


^■i'  B 


ji  : ' 


^ 3' 


,it;, -'  . -\  . "-  ...  \ 

.v.-r:';-'.  ' ... •■..*••■»-.  ,N 


'“•■tO  » J I -T  j ■ > V J *:t 


.,  ,1  r.?^' ■■■■' 

If*  ' *jf  I * ", 


r>  ^ 


i f '<7  ■'  /'*  r V "V  , 


iL..;.,  'A.  ..  ..  .,. 

' HS*  Vv'-.; 


.■i:.'-C^!^ 

•>i>l^5|I.> 


- - ■^■^•\  » - ••»•  - ^ >• 


.::^fcr  T.i:;^;S5=*S)X- 


' 


i<gr::^TO\-*rBatoy3iswy^^ 


k\  A.  ' 


14 

If  the  condensation  product  from  arsanilic  acid  has  the  structure 
V,  it  will  00  the  first  compound  of  this  type  to  he  isolated  and 
it  may  give  additional  information  concerning  the  course  of  the 
reaction  between  aryl  amines,  pyruvic  acid  and  aromatic  aldehydes. 

In  conclusion,  it  may  be  said  that  altho  the  structure 
of  the  compound  formed  by  the  condensation  of  arsanilic  acid  with 
pyruvic  acid  and  benzaldehyde  has  not  been  definitely  established, 
between  formulae  II  and  V,  the  formation  of  one  mole  of  carbon 
dioxide  on  heating,  the  splitting  off  of  aniline  on  alkaline 
fusion  and  the  regeneration  of  arsanilic  acid  on  treatment  with 
aniline,  are  facts  which  are  more  easily  explained  on  the  basis 
of  the  latter. 

Limitations  of  the  Reaction 

With  the  idea  of  studying  the  limitations  of  the  re- 
action between  aminoaryl  ar sonic  acids, aldehydes  and  pyruvic  acid, 

a series  of  reactions  was  carried  out  oetween  substituted  arsan- 
ilic acids  and  aldehydes  with  pyruvic  acid. 

It  was  found  that  arsanilic  acid  and  pyruvic  acid 
yielded  the  desired  condensation  products  with  all  of  the  aromatic 
aldehydes  tried.  These  included  o-  and  p-methoxy,  p-halogenated, 
p-dimethylamino,  and  o-nitrooenzaldehyde^  No  condensation  products 

were  obtained  from  paraldehyde  and  n-'ctutyraldehyde. 

When  o-substituted  aminoaryl  arsenic  acids  were  used 
a condensation  took  place  to  give  benzylidene  derivatives  of  the 
amine,  but  these  did  not  react  further  with  the  pyruvic  acid  even 

1 


hi 


■YFJ  i ■.■H‘ ■ •■  ■”*  • r ’ ' ^ “^fT'l 

: '-  ~^-s./;«g  -^srsxixd^^sfcrjsrtas^  77ta)^;r*cyar.;jH 


-n 


15 


ttii.7  »i;ir:  !:iOr  i.l.  t fi:  \l 

■■'  -.7#  t-b  AflfifC)'3^<?r..  X'Xi* 


• '•■•  -I^.  • (' . o> /j^r-A •■  gvi^J 

'*.,lf^  ' /•'if  '’  •ji'-'t'ijf.c;  .rvi '.."^ 

> . ^ ' . 

.'  1 <■■  ' *i  '»  .'ff*  l>rr*Q  0<5  Xvj'"}  ~^:’*^i^'^^LtCQp/  f£^  - 

■ -,  ' ’ *-ff.(r.i:)C^Dri  yn'  ’jf  I '<rrt>fj/(Blo^^' 

^ A- 


*v 

4-  .. 


, s / ^ 


z.^v  z 

i 

:;  fL.Ui^,  •' 

xt^/  ‘4.^ 


j/:;-?.  IT  Gi^jSni^^5:  V— 


<9 


•i*  i *•  n Ir/A  j.  ■ ^ . 


;-'‘c^  :6  'K' 

»r 

'M 


no  45-T-*  '■  tTf 


I . a 


, % 


, Wf  J 


(A 

’ X'  - 


‘ :\  ■ ■ ^ . ■ V^"  . 

• -^■-  ■■  - " ' ■■■■  . - .<.•/*''  /.  -: 


^ ^ *5  %-[  4:  i'04»  ?*4  i ’•>',f'r'n:'f‘-  j , 

, "f»;  ?-  i 5"-'i:7V|  f'  .:•  i^» -'•/;■  i\.io-' ssifff  X'et»Xe'i^t‘' jy 


- ^ '^'  ',  '-I® 

■ i-'v  '•.■  ■ ••  >j5-r 00 71/ "O 


li  X 


*.  V *'  Vf-*'- 


«* 


/r^  ^1% 


f\  i^f:.  t '. 


. ' - ' ”••  . . .'  >:  ' If' 

* ' , ,■  . A .Tii.;''.  ■•■’  ' ~ ' - lj¥'- 

■ '■  - ■■:  ; 


-I'T  " 6 }■■ ’.--y z‘: i'V  <&crnlli-‘-rrr\'s!,  ayh*  ^v?‘  -^’i-i ) 


^1 


"jf 


-.r  .a.  .i 


•r4rJC3Ciuy3XB«cn;ia» 

¥3 


•.i',.,  .•  if‘, )i. 


J&A'&H*  l‘'lll  , J , ' .t  / I K 


IS 


on  long  heating.  The  substances  used  for  these  experiments  were 
o-arsanilic  acid,  3-methyl -4-aminophenyl  arsonic  acid,  and  3- 

bromo-4-aminophenyl  arsonic  acid.  These  results  are  in  accord 
with  those  of  Borsche,  who  was  unable  to  obtain  condensation 
products  from  o-ohlorc,  and  o-nitroaniline^® , 

\*/hen  m-substituted  atninoaryl  arsonic  acids  were  used 
the  condensation  occurred  in  the  usual  manner,  and  good  yields  of 
the  desired  products  were  obtained.  The  particular  acids  used 
for  these  experiments  were  2-inethyl-4-aminophenyl  arsonic  acid,  and 
3-methoxy-4-a>]-iinophenyl  arsenic  acid. 

These  experiments  lead  to  the  following  generalizations: 

i.  The  reaction  is  general  for  aromatic  aldehydes,  but 
not  for  the  simple  aliphatic  aldehydes, 

ii.  The  reaction  takes  place  with  substituents  in  the 
ffi-  and  p-positions  in  the  amdnoaryl  arsonic  acid,  but  does  not 
occur  when  o-substituent s are  present.  In  the  latter  instance, 
benzylidene  derivatives  are  formed  which  ao  not  react  further. 


’I'  f, 


’ «V  ^31 

r--.  -,  .i'-r-tfN'# 


^1.  , , 

T7>»y 


<1  r 


P 


L 


i 


1^  .* 


.7', 


i T-V*  J 

r 


/'I  •’fee-  V';*’-"  *T0,  ' ' t- : ‘ .’.T 


'■  • ^ 


^ ui:^:  ^-'  . -;i^  * X»-'  '.f.  -'-'jj-:.'  *f/  - - !.\},  :*•■»-£  iw  7^;X'X''45lEr- 

f.i:  <'*.'•  *>rr  C . ^J^ca 

' v^*.  '■  *‘';.V  ^ •.  '• 

' . f^r.  j;'-j  L>;  Vi;-  .V  s?*'*  *'•  *io  oj  iff ji^ 

. ■■  > *<  '■  /•'  ‘ - 


iU. 


.;.r  ’ . ."5*"  J/jB-'’)  .' 


» - « V, 
t • 


-o  tpL 


^.1  *L  . V *,'  i t ^(. , , ' . ' ••  H ♦ < » ■'  ■ £^0  •" (V 


^ M'.ji-r  zi:-  l i m k^l:  ■ i.atpisiot^ 

k 

ij^-'  /c**j  <\. ’L' '•■' -i’~  o«^^v■  kfs'sl^id  Xe*i3»St  ^;’;- 

■ .j  ■ 

•:.2  I I'ijf' ■ ■ .•  r ^v!' •6s>rf3?  .^ol 

I . - ^ A .'  t , i? 


i.'^  .-Li',, .:  .'i-.'l  r..-j  v*  '■"'''V-^  >.- ^'f  • ^*'3* 


. » 7' 


![  "1 , c ^ r .Xffoisca  ,.  ^ ’’i.,v-i 

/j 

, ' •.. fr,  * i-1tJ>  \i  ii? 5>  - a’fft  lol  ^ 


i'-ai  .t‘i  ■ i n?*  ' rn.i;i: 


J.  * /’ .'  i. 


‘ ^ ’..'.t  aJ 


'I  ■ 


* r *f 


I 


, '.'  . V-'  * " 

*,z^  . f f> V i f “ Vi. o^g^,.. 

' ,;'"  iff ' -1 


■■'*’■•*-  • ■ •— - ■,-asrr;-:iflS' 


‘-isssssr  ',  ;v-taarrr7fc«5iu  r..:-^««^^^ 


16 

III.  EXPEREIF’NTAL  PART 

The  experimental  work  is  divided  into  three  parts: 
first,  the  preparation  of  substituted  aromatic  arsonic  acids; 
second,  the  condensation  of  arainoaryl  arsonic  acids  with  aldehydes 
and  pyruvic  acid;  third,  the  constitution  and  reactions  of  the 
condensation  products, 

A,  The  Preparation  of  Arsonic  Acids  by  the  Bart  Reaction 

This  reaction  has  been  extensively  used  for  the  syn- 
thesis of  aromatic  arsonic  and  arsinic  acids,  and  various  modifi- 
cations have  been  used  in  specific  cases.  For  the  nitro  substi- 

X B 

tuted  amines,  the  procedure  of  Rchraiit  is  found  to  be  quite 
satisfactory  and  was  used  in  preference  to  that  of  Jacobs,  Heidel- 
berger  and  Rolf^^.  The  yields  have  been  found  to  vary  considerably 
when  only  slight  changes  were  made  in  the  procedure.  For  this 
reason  the  method  employed  is  given  in  detail. 

General  Proced^urei  1 mole  of  the  amine  was  dissolved  (or  sus- 
pended) in  600  cc,  of  5-N  hydrochloric  acid  (3  moles),  chilled  by 
the  addition  of  ice,  and  diazotized  bv  introducing  a solution  of 
1 mole  of  sodium  nitrite  through  a dropping  funnel  extending  be- 
low the  surface  of  the  liquid.  With  good  stirring  the  nitro- 
amines  dissolve  almost  cortpletely  in  the  course  of  10  - 15  minutes. 
The  diazo-solution  was  filtered  from  any  insoluble  material  and 
transferred  to  a large  container  of  13-15  liters  capacity.  It 
was  thoroughly  chilled  by  the  addition  of  ice,  and  a few  cc.  of 
isoamyl  acetate  added  to  cut  do'im  the  frothing  when  the  arsenits 
was  added  later. 


17 

With  good  stirring  300  cc.  of  5-N  sodium  hydroxide 
(1  mole)  was  added,  followed  at  once  by  a mixture  of  750  cc.  of 
2-N  sodium  arsenite  solution,  NajHAsO^ , 60  oc.  of  5-N  hydrochloric 

acid,  650  cc,  water,  650  g.  ice  .and  300  cc.  of  30fc  copper  sulfate 
solution,  added  immediately  before  using.  The  addition  of  the 
copper  sulfate  caused  the  formation  of  a green  precipitate  in  the 
arsenite  solution.  When  the  arsenite  solution  was  added  a vigor- 
ous evolution  of  nitrogen  occurred  and  unless  the  reaction  mixture 
was  thoroughly  agitated  the  froth  almost  filled  the  container. 

After  allowing  the  mixture  to  stand  for  an  hour  it  was  warmed  to 
40-50^  and  filtered.  The  clear  filtrate,  which  was  neutral  or 
slightly  alkaline  in  reaction,  was  acidified  to  litmus  with  acetic 
acid,  concentrated  on  a steam  bath  and  filtered  hot  to  remove  a 
yellow  flocculent  by-product.  The  filtrate  was  treated  with  hydro- 
chloric acid  until  acid  to  Congo  paper  and  the  arsonic  acid 
separated  out.  The  precipitate  was  filtered  with  suction  and 
washed  thoroughly  with  water.  For  most  purposes  the  crude  product 
is  sufficiently  pure  without  further  treatment. 

Prepared  by  dissolving  198  g.of  arsonic  trioxide  in  800  cc.  of 
5~N  sodium  hydroxide, and  diluting  to  1000  cc. 

Attempt  to  prepare  Quinoline-6-Arsonic  Acid;  6-Nitroquinoline  was 

7 

prepared  by  the  method  of  Knueppel  , from  p-nitranilin,  glycerol, 
arsenic  pentoxide  and  sulfuric  acid.  For  reduction  to  the  amine 
it  was  found  advisable  to  use  the  purified  nitro-compound  and  not 
attempt  to  reduce,  the  crude  product. 

The  reduction  of  6-nit ro quinoline  to  6-aminoquinoline 
was  effected  by  means  of  powdered  iron  and  a small  amount  of 
acid.  The  crude  dark  product  was  purified  by  vacuum  distillation, 
and  the  product  was  oDtained  in  pale  yellow  crystals  which  darkened 


'j-v-  ^ 


^*rt- 


V r>  1,  =■■  - ,,  I || 

• Ti"%r  rr5iRsr:'»ts:“t;5xti. 


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'. ‘ o-i  -*'i  ‘•'i’f'-s  ^£0  . .•  O'j^:  ibo^ 


1 


"jo  ?fP  (rflfc:  X) 

o^?^v.  >!..■?  t>,  .*::  00  , t!*' '«{rX>oa  2-t 

'■  ^v.Ji.''/  'V'  '^0  ,00  OwL  hnjB,  roJt""  .■  .vC  ^ : * 

» t:  tl'ir  fta^‘  .:;ai-.'^  '^nb^^e''  v*^' 

:•  r *;:  >’  iiaiitiiiV.TO  fcJr^PV.O 

:.  [’'L'-Xoia  0-ti.itT*?-!?  ' -'I*  na;'"  , '»3“X»S4»-1;S 

. -air  /•!  ^ . iwi*i  craTJfX-O^*  a^  -vWtx^  Xo  4>tfo 


• . : ij-  I ' ■ *■.  • tf: 

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* * - • t ‘ -*  *3^ ' 


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; L'*-  ' '7.,, - 

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•■'..•SI  • •■•,  >.-.  tl^inyiv.  txdln  -fcXfia 


• j;  ' X* 


>/ 


1 e 

on  exposure  to  the  air.  From  35  g.  of  nitroquinoline,  the  yield 
of  amine,  h.p.  169^-176°  at  5-6  mm,,  was  18-30  g.  which  is  60-70^ 
of  the  theoretical, 

15  g.  of  S-arcinoquinoline  was  dia2Jotized  and  treated 
with  sodium  arsenite  according  to  the  above  procedure;  an  evolu- 
tion of  nitrogen  occurred  and  a thick  bro’-m  material  was  formed. 
From  the  filtrate  after  concentration  and  careful  neutralization 
no  quinoline  arsenic  acid  could  be  isolated.  On  evaporating  to 
dryness  and  extracting  the  salt  with  alcohol,  no  arsenic  acid 
could  be  obtained  from  the  alcoholic  extract.  The  reaction  was 
repeated  'JFith  the  same  result,  and  was  then  given  up, 

2~Nitrophenyl  Ar sonic  Acid;^^  38  g.  of  pure  o-nitraniline  ^vas 
finely  pulverized  and  diazotized  at  10°,  and  the  diazo-solut ion 
treated  with  sodium  arsenite  according  to  the  general  directions. 
The  product  separated  out  in  pale  yellow-white  needles.  The  yields 
were  good,  varying  from  38  -43  g. , which  is  75-85^;  of  the  theor- 
etical. The  product  was  sufficiently  pure  for  reduction  without 
further  purification. 

4-Uitrophenyl  Ar  sonic  Acid^^  ; 38  g,  of  technical  p-nitraniline 
was  diazotized  at  10°  and  treated  in  the  usual  manner.  The  p- 
nitrophenyl  arsonic  acid  was  obtained  in  the  form  of  pals  yellow 
crystals  weig^iing  38  g,  or  53^  of  the  theoretical  amount.  This  is 
slightly  better  than  that  claimed  by  Jacobs,  Heidelberger  and  Rolf. 

3~Methoxyphenyl  Arsonic  Acid;  13.3  g.  of  pure  o-anisidine  was 
diazotized  at  0°  and  treated  according  to  the  general  procedure. 

The  crude  o-anisyl  arsonic  acid  separated  in  slightly  yellow 


^ T •F.ir 


, S.X 


n''  h 


- % 


* 'j 


I' -I 


Jiii9 


: r. 


X:  iLj,^ 

©rf# 


•. •'  tvl  .'•■r:*  - 


'5  j rU 


J! 


1 fcj  'I  i ; . 


, ^ 

.<  ,i.  .» 


r»  '•* 


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'J 


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0 ' “J  • 1 '■  ■ .^ 


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: J ■ V 

.:-=35i:.  vi,i  ; - ^ :• 


ti: : r 


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. t:foS 

■ 7 

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/-V 


\ 


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j VT''' 


1 ■ 

"-'  _ j^'p  • — ; , \ i r**- 

■ -'^r...  ■%..  ..  y tL 


"I*  a 


.1 

.jt 


19 

flocks  and  after  drying  weighed  15-J-  g,  which  is  65^  of  the  theor- 
etical amount.  The  o-methoxyphenyl  arsonic  acid  crystallized  from 
alcohol  in  beautiful  white  needles,  ra.p,  1S3°-194°. 

Sub#.  0.2000,  0.1995  required  21.50,  21.48  cc.  of  0.0808  N I. 
Calc,  for  C7H9O4AS:  As,  SB.Slfa,  Found:  32.57,  32.59*yt-. 

This  acid  is  insoluble  in  cold  water,  soluble  hot;  slightly  soluble 
in  cold  alcohol,  quite  soluble  hot;  insoluble  in  ether  and  organic 
solvents.  It  is  readily  soluble  in  aqueous  alkalies,  carbonates 
and  ammonia, 

24 

4-Methoxyphenyl  Arsonic  Acid:  Michaelis  prepared  this  acid  by 
the  hydrolysis  of  p-anisyl  arsenic  chloride,  and  Bertheim  ob- 
tained it  by  the  methyl at ion  of  phenol  p-arsonic  acid.  It  may  be 
readily  prepared  from  p-anisidine  by  Bart's  reaction,  and  was  ob- 
tained in  35^'o  yield  from  technical  p-anisidine.  It  was  crystallizec 
from  water  and  was  found  to  melt  from  173^-177®,  Bertheim  reports  ; 
I79O-I8OO. 

2 2 

6-Methyl-2-Nitrophenyl  Arsonic  Acid  : The  nitro-toluidines  used 
for  the  preparation  of  the  corresponding  nitrotolyl  arsonic  acids 
were  prepared  through  the  nitration  of  o-acetotoluide and 
separation  of  the  isomeric  nitro-acetotoluides  by  the  Witt-Utermann 
metiiod.  The  method  of  Reverdin®*^  and  Crepieux  was  tried  for  this 
separation  but  was  found  to  be  less  satisfactory. 

30-J  g.  of  3-nitro-o-toluidine,  CH3:l:NHg:2,  was  diazo- 
tized  and  treated' with  sodium  arsenite  in  the  usual  way.  The  fil- 
trate after  acidification  with  acetic  acid  was  concentrated,  and 

* All  analyses  for  arsenic  are  by  the  method  of 
Robert son^^ , unless  otherwise  stated. 


■»  r 


1 


i . . ..A 

1 

. i ' < »<i  ► r t 


!l 


r 


j 

! 

! f 


so 

filtered  from  the  yellov/  floccrulent  by-produot.  This  clear  fil- 
trate on  cooling  deposited  a crop  of  pale  yellow  needles.  A 
sample  of  the  latter  was  collected,  washed  with  alcohol  and 
examined.  It  was  found  to  be  the  mono-sodium  salt  of  the  nitro- 
tolyl  arsonic  acid: 

Subs.  0.2197  g.  required  17.13  cc.  of  0,0893  N I. 

Calc,  for  C.,H,y05NAsNa  : As  = 26.50f^  Found: 

for  C^HeOgNAsNa  : As  = 34.  58fc  As  • 28. 19?^^ 

This  salt  is  moderately  soluble  in  cold  water,  quite  soluble  hot; 
it  is  very  slightly  soluble  in  alcohol  and  ether.  The  crystals 
which  separated  were  redissolved  by  heating  and  dilute  hydrochloric 
acid  added  to  acid  reaction  to  Congo  paper.  The  S-rcethyl-3-nit ro- 
phenyl  arsonic  acid  separated  in  white  flocks  and  weighed  40  g. 
or  75fo  of  the  theoretical  amount. 

8-L^ethyl-4-Nitrophenyl  Arsonic  Acid^^:  From  30^  g.  of  5-nitro-c- 
toluidine  there  was  obtained  25-26  g.  of  this  arsonic  acid,  in 
pale  yellow  flocks.  This  is  only  50^o  of  the  theoretical  yield, 
the  difficulty  in  this  case  apparently  being  incomplete  diazoti- 
zation  of  the  amine. 

2-Methoxy-4-Nitrophenyl  Arsonic  Acid:  The  p-nitro-o-anisidine, 

NOs, 4;0CH3, 2jKHa,  1»  used  for  this  synthesis  ms  prepared  through 
the  nitration  of  o-acetaniside  and  separation  of  the  resulting 
mixture  of  m-  and  p-nitro  derivatives®®.  123  g.  of  pure  o-anisi- 

dine,  b.p.  99®-103°  at  S-9  ram.,  was  heated  to  boiling  ’-vith  105  g. 
of  acetic  anhydride  and  33  cc.  of  glacial  acetic  acid.  The  solu- 
tion was  placed  in  a 1^  1.  flask  provided  with  a good  mechanical 


ll 


w-r 


i 

I 


31 

stirrer  and  rapidly  cooled  by  immersion  in  a freezing  mixture.  A 
solution  of  65  cc.  of  fuming  nitric  acid,  1.52,  in  90  cc.  of  cold 
acetic  anhydride  was  added  during  the  course  of  four  hours,  keep- 
ing the  temperature  below  0°.  After  the  addition  of  the  nitric 
acid  was  completed  the  mixture  was  allowed  to  warm  up  slowly  to 
room  temperature  and  stand  for  36  hours.  The  red-brown  solution 
was  then  poured  into  a mixture  of  1300  g.  of  ice  and  water  and  a 
yellow  precipitate  of  the  mixed  ra-  and  p-nitro-acetanisides 
resulted.  This  was  filtered  with  suction,  washed  thoroughly  with 
water,  and  dried  in  the  air.  The  yield  was  208  g.,  which  is  almost 
the  theoretical  amount. 

The  crude  reaction  product  was  hydrolysed  by  warming 
on  the  water  bath  with  a mixture  of  350  cc.  of  concentrated  sul- 
furic acid  and  650  cc.  of  water.  With  occasional  shaking  the 
material  dissolved  and  after  1-1-^  l^ours  the  solution  was  poured 
into  a beaker  to  cool.  The  solution  was  then  chilled,  and  the  re- 
sulting paste  of  the  sulfate  of  p-nitro-o-anisidine  was  filtered 
with  suction  and  pressed  as  dry  as  possible.  Without  washing,  the 
precipitate  was  transferred  to  a beaker  and  thoroughly  mixed  with 
cold  water.  This  caused  the  hydrolysis  of  the  gray  sulfate  to 
the  free  base.  The  bright  yellow  base,  ^ ^”2  was  filtered 

with  suction  and  dried;  m.p.  136°-139^  (recorded  in  the  literature, 
m.p,140O). 

The  yield  was  102  g.  or  60^  based  on  the  anisidine 
used,  and  for  ordinary  purposes  the  crude  product  is  sufficiently 
pure.  Impure  ra-nitro-o -anisidine,  ^oc  H^was  obtained  on 

neutralization  of  the  sulfuric  acid  filtrate  with  ammonia;  the 


f-7  ^ 


' a 
-r 


,•  tay:U  -i'.i  iV..^  Vci  IJC'Idbo  ■ wu 

0 ■.  . ^ - tx^Duiot 

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c;l  .‘,  liaejB 


•■'v' 


.*fr  I.F  i / . .'v»f’j‘  ’‘0  V fr^r-iiff  n5dl;^ 

’ , I 

> f« 

fVi.U.  -.i  H'C  - 'r*  - 10' et- woUev' 

■ , 'i  C;  / *"  V - ^ 


\X':  *..’r’  ..\tiv»'  ax?wp  lire 4iir  i^.' 

' (TW» 


T t'v,  iili  lT  / ,’->x^  §.’?  at  bfil'w 


-■••  »'c  t?j  . 


■,j.rr.  ‘ b j.  :■  'i/,oxq  tvif'xo?A*r 


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\b  .wO  G'5^  taB  ijJto^v  oitil 

• ■ ^ .,  .■•’■^^.,  . i/iti  . ^ 

I~1 


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■ '-5*-  \ ’ 

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v> 


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’y 


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. . ■ ; f4i>l7li  tsu’  adl-om  J ’; 

' 'jfv: 

' . , ; •(®o*4-:V.a1 

• ^ I » „ ■ kV'*  f 


:;0  tfi'BPC/  ,Ha  ip  ..-  -feOl  £!'»♦'  ii4ifl\f  Bt#T  .. 


' 


■;jLj  uJt  b».‘?3u5  , .•..■0tt6C;W; 


.■*1; 


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< c ^ri0h  t A*J?- p-  ^ 4- w;i^ r ‘^l  ► ©l tr^. 

■ iv  ■,  , -^''  _■  . - ■'^-5 ‘V  ', 


:«.tao3'  ,r  '! ithf  efiUt. 

^ ■;'  ' T tt  1 


rm. 


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. - ' .4..  , • 


22 

amount  was  55  g.  or  33fo  based  on  the  anisidine.  It  was  found  that 
the  above  procedure,  whereby  the  acet-o-aniside  was  not  isolated 
gave  an  increase  of  5-10^  of  the  product. 

33-^  g,  of  finely  pulverised  p-nit ro-o-anisidine  was 
suspended  in  hydrochloric  acid,  diazotized  end  treated  with  sodium 
arsenite  in  the  customary  way.  The  p-nit ro-o-methoxy  phenyl 
arsonic  acid  separated  in  small  pale  yellov/  needles  and  the  yields 
were  30-32  g.,  which  is  54-58fo  of  the  theoretical  amount.  This 
arsonic  acid  is  very  slightly  soluble  in  cold  water,  more  soluble 
hot;  it  is  soluble  to  the  extent  of  6 g.  per  ICO  cc.  in  boiling 
905^  alcohol,  and  crystallized  on  cooling  in  aggregates  of  long 
pale  yellov/  needles;  it  is  insoluble  in  ether  and  organic  solvents; 
readily  soluble  in  aqueous  alkalies  and  ammonia.  It  does  not 
melt  up  to  250®. 

Subs.  0.1987,  0.2060  reqmred  17.56,  18.27  cc.  of  0,0808  N I. 

Calc,  for  C^HgOgNAs:  As  = 27.08f.;  Found:  As  - 36.78-^/^,  26. 86?., 

The  Preparation  of  Aminoaryl  Arsonic  Acids 

There  are  two  general  methods  of  preparing  the  amino- 
aryl arsonic  aoidp: first,  the  reduction  of  nitroaryl  arsonic  acids, 
and  second,  the  direct  arsenation  of  aryl  amines.  The  first 
method  is  very  general  in  its  application  and  has  led  to  the  syn- 
thesis of  a large  number  of  amino  arsenic  acids,  especially  o-  and 
m-  derivatives.  The  second  method  is  of  limited  application  and 
is  used  chiefly  for  the  preparation  of  p-aminoaryl  arsonic  acids. 


33 

The  Reduction  of  Nitroaryl  Arson! c Acids  ^ 

The  reagents  'Jirhich  have  been  used  for  the  selective 
reduction  of  these  acids  are  ajiunoniura  sulfide,  sodium  hydrosulfite, 
sodium  amalgam,  iron  powder  and  alkaline  ferrous  hydroxide.  The 
last  was  used  by  Benda^® , and  by  Jacobs,  Heidelberger  and  Rolf. 

A modification  of  the  method  of  the  latter  authors  has  proved 
quite  satisfactory.  The  substitution  of  ferrous  chloride  for  the 
sulfate  is  of  considerable  advantage,  since  this  obviates  the 
troublesome  precipitation  and  filtration  of  barium  sulfate. 

General  Procedure:  A solution  of  ferrous  chloride  was  prepared  by 
treating  an  excess  of  powdered  iron  with  hydrochloric  acid  and 
heating  on  a hot  plate  until  no  more  gas  was  evolved.  This  solu- 
tion was  kept  over  metallic  iron  until  just  before  using,  and 
after  filtration  its  ferrous  chloride  content  was  determined  by 
permanganate  titration. 

A solution  containing  7 equivalents  of  ferrous  chlor- 
ide was  placed  in  a large  wide  mouth  bottle  fitted  with  a rubber 
stopper,  and  after  thorough  chilling  by  the  addition  of  ice,  a 
cold  20^  solution  of  sodium  hydroxide,  14  equivalents,  was  added. 

In  the  meantime  a solution  of  the  di -sodium  salt  of  the  nitro  acid 
was  prepared  by  dissolving  1 equivalent  of  the  nitroaryl  ar sonic 

acid  in  1000  cc,  of  2-N  sodium  hydroxide.  The  solution  of  the 
nitro  compoiind  was  added  at  once  to  the  pale  green  jelly  of 
ferrous  hydroxide.,  and  the  bottle  stoppered  and  vigorously  shalcen 
for  10-15  minutes.  The  color  of  the  mixture  changed  from  green  to 

brown  and  after  standing  a short  while  with  occasional  shaking  the 
mass  was  filtered  with  suction  on  a large  funnel.  The  paste  of 


7aserr--r- — 


%'W  rfji 


•'  •,  « zcfl  Ja-  p.  .vQ-C'^;<r-.  j 


' •■  jivfc 

• * .-•  i:  Ltbi,' 

Fps^-T 

-V'l 

**  f iiM 

.e^'vOiiL  yc  li\i  •(<■'  tirw  . o* 


lie 


’.  to  ,Uf.  a>,'..  drtn  OiJIi'  exi^/> 


v}*^  ti<  ■ 


."r.'^^'r*/  .,.:f.:;^i a;- 1^.  la'.r  JzX^yBdl-dlpi' z, 

. .^i  ■'■ 

">j  iitl  KiI.Qb  ’■  -a: 


- •?  :ydl/u  ur 


»r-  , 


£•:  .n 


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?V  ■;  V ;!  %)/■  \i:y*:  ‘ . i*X/'  X^. 


>vi 


/,v'..:’  d'tzts'tr^.  if  vip^  r*oir 


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I . 


s/i,U‘if  V .,-i;  Jr/i^iTc:  i 4 

> * 'i, ( 


(V^  i 1 


.'  ,-..tiv  it  f‘v  i ♦ t fbiy  f.,;:^.I  . ! b eDr 

•.•>i  ;4..ix^  Siij  rrf  ?.c  fifto  IS*  ^^ecg|o;te 

,t  A,  oa^-r^fc  ’J:i  i?o  ' :‘S?Xp®^OC 'bX<?0 

' -i-  "-  t Xf  s mi  U:Vd-^if^  f^W  Iq 
fv  * : ' “.  * ".-:  'iff. 7.  ':«•  X Jn'ivri?4-R  ii,  •-:  ^ 

^ r‘l,rO^  .‘i!>  OOO'IV-fti  <4&'S 


-J  v.ii'  ' • ' «-r  fixtj  cjff  OO^JO  >V*  / etf/it’ 


. V ■ m;c  * 0 /..V  ■''■  ■' f-'ic; 


A-X':  ;rc- o'  .< 1^ 


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•;  .'‘  U'v'xX'''  V'.'-i?  'io’lqo  UX^OX,  w,« 


rt  . 


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».iy  :-:&=£g?;^  j»??3«!.itas^  ' lalictf  J 


' ^3  ; ; .. 


34 


ferric  hydroxide  was  sucked  as  dry  as  possible  and  then  discarded. 

The  alkaline  filtrate  was  concentrated  on  the  steam 
bath  to  a volume  of  700-750  cc.,  filtered  from  sodium  chloride 
ajid  the  filtrate  further  concentrated  in  vacuo,  20  mrn.  When  the 
volume  is  quite  small  the  solution  was  treated  with  decolorizing 
charcoal,  filtered  and  cooled.  Dilute  hydrochloric  acid  was  then 
carefully  added  to  the  cold  solution  until  it  just  reacted  acid 
to  Congo  paper,  and  the  amino  arsonic  acid  precipitated.  The 
products  usually  had  a yellow-pink  color  and  were  purified  by 
crystallization  from  water. 

2-Aminophenyl  Arsonic  Acid,  o-Arsanilic  Acid^^;  Using  40  g.  of 
o-nitrophenyl  arsonic  acid  and  following  the  directions  outlined, 
24  g.  of  o-arsanilic  acid  separated  in  slightly  pink  crystals, 
m.p.  150^-153^.  This  is  70Jc  of  the  theoretical  amount,  and  is 
slightly  less  than  the  yield  obtained  by  Jacobs,  Heidelberger  and 
Rolf,  but  their  results  could  not  be  duplicated  in  this  labora- 
tory, 

2-Methyl -8-Aminophenyl  Arsonic  Acid^^;  The  reduction  of  26  g.  of 
2-m ethyl -S-nitrophenyl  arsonic  acid  gave  12  g.  of  crude  amino 
arsonic  acid.  This  material  was  crystallized  from  water  and 
melted  from  173^-175®.  The  yields  were  50-55^  of  the  theoretical, 

2-Methyl-4-Aminophenyl  Arsonic  Acid^^:  From  26  g.  of  the  nitro 
acid  by  the  usual  method  of  reduction  were  obtained  12-15  g.  of 
the  crude  amino  arsonic  acid,  m.p,  216^-220®,  This  is  50-60^  of 


the  theoretical  amount 


r i 

it  r 

r ,u  *1 ‘ 


f 


..  tl-i";  03-bv/^ 


It.  m, 

<w 


j.  ' 


i'  : 1 . rv;iH'  iTfriTi^  viHf-m  ^ ’ S"  • 

U;  Or-f-'X"  V< ' «fitrX9T-1i  rltV 


,oynav  i.:  ■'  .^^-;rD©  WiS.’p:;.  ^trl^  m 


.sa .( 


. . , • . , ,-,  >t  1#  »* 


Ic  ;o  t>r^ 


■ i*'  •'  • iQ*  titjt:<  sji 

» ■'''/  if  p ^ i i|  ■ « . 


:,  u ’.."  c ':*  tu‘  »*{.• 


5C 


• Ci 


^ 03 

<r " 

.' ,.rxt»Y  I**  - ' 

V_r  •-'  ~ 

,r  r o;i% 


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- ' V — — 

^’*i5  t» ; /-i  '•  ■; 

' ■■•.  1.,'^  ^L. 


" . ,■  jr 

. 5 I St  fl . V H t a fc-0  ; TO  " . 


* ? * ’ 
. \Q  >V  ; 


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,ic : M 


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;.  'vv  :r.,''  'v^'-i*''. 

■ ‘-"i. '/at!  iO'  ► IX 


*•♦■.,  ;• 


i X*»:  Cl  -.  /■  *“'  ^-X’l  *'.’  »'hj}/-'f. 


Ck-O'-a^  'v>. .; 


-rf 


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•it'  1.  .*-,.1  ::/.  Oilt 


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• ' '*• 


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CX"  /'  fli6» 

■ > '-^'r 


. if X#^'  i 3es  i'0^4^'  <^-5^ 

‘ ‘ t ■■■  ■■  -,-_  _ : 


/ 


V' 


m ’ 


25 

2«jiothoxy"»4~Aminophenyl  Araonlc  Acid:  Derivatives  related  to  this 
substance  have  been  prepared  by  the  arsenation  of  carbethoxy  ra- 

42 

arainophenol,  and  by  the  use  of  5-nitro-S-arninophenol  in  the  Bart 
reaction.  The  methyl  ether  can  be  most  conveniently  prepared  by 
the  reduction  of  3-methoxy-4-ni trophenyl  ar sonic  acid,  obtained 
through  the  Bart  reaction. 

38  g.  of  the  nitro  ar sonic  acid  was  dissolved  in  300 
cc.  of  N-sodiura  hydroxide,  and  reduced  in  the  usual  way  with 
ferrous  hydroxide.  The  impure  material  was  obtained  as  a brown 
crystalline  precipitate  amounting  to  13-13  g.  or  SO-oO'^  of  the 
theoretical  yield.  The  3-methoxy-4-aminophenyl  arsonic  acid  v/as 
crystallized  from  water,  and  was  obtained  in  beautiful  whits 
needles. 

Subs.  0.1503,  0.3000  g.  required  15.07,  20,32  cc.  of  0,0608  N 
Calc,  for  C7H10O4NAS:  As=30,33f^.  Found:  30.38^b,  30,S5f.. 

This  acid  is  slightly  soluble  in  cold  water,  more  soluble  hot; 
almost  insoluble  in  alcohol,  ether  and  organic  solvents.  It  dis- 
solves readily  in  alkalies,  carbonates,  and  ammonia,  and  in  mineral 
acids.  When  heated  rapidly  it  melts  at  208°-209®;  heated  slowly 
it  melts  from  303^-204°. 

Preparation  by  Direct  Arsenation 

5-Methyl-4-Aminophenyl  Arsonic  Acid:  This  acid  is  readily  prepared 
by  the  Bechamp  reaction  from  o-toluidine^°  and  arsenic  acid.  The 
method  used  was  a modification  by  W.  Lee  Lewis  for  the  preparation 
of  arsanilic  acid.  The  crude  o-toluidine  arsonic  acid,  which  was 

slightly  pink  in  color,  was  purified  by  precipitating  the  mono- 
sodium salt  from  its  aqueous  solution  by  pouring  into  absolute 


’ r 


r, 


ii 


t 

) 


I 

I 

) 


V 


ij 


i 


; \ 

I 

■* 


♦,  vriv 


i h 


;u ;. . 


.i-c* 


'I 

-•it! 


:v£f  .'I 


l-'I  1 

. ! Bi  ^ . 


< ' *Iv»’ 


-'■  • - I . 9;  -f'v' 

r , Ei; 


I * /r.r 


-t  g;;:*:' 

c-tvi  ;?■•■ 


i. 

:f 


; .Ct.itt  V 


j ..  ■■./ 

i 


. 2', 


;.  : Lit-- ^ ...- 


n 


' is 


r 

-\j  j 


'-'i-’l’w 


I 


86 

alcohol.  It  separated  in  large  white  crystals,  containing  3 0, 

and  not  3-^  HsO  as  stated  toy  Pyraan: 

Suds,  0.9700,  1,2576  g.  heated  at  130^  lost  0.1718,  0.2315.g 

Calc,  for  CvHeOaNNa,  3H3O:  17,59f.  Found:  17,7^c. 

C7Ha03NNa,  3-^H  0:  19.94fc  17.63f^. 

The  free  acid  was  obtained  on  adding  the  calculated  quantity  of 

hydrochloric  acid  to  a solution  of  the  sodium  salt.  It  separated 

in  white  leaflets  or  plates,  ra.p,  195^-198®, 

5~Bromo-»4-Aii!d.nophenyl  Ar sonic  Acid:  Although  the  halogenated 
anilines  may  toe  used  in  the  Bechamp  reaction,  it  is  usually  more 
convenient  to  prepare  the  halogenated  aminoaryl  arsonic  acids  toy 
indirect  means,  Bertheim®''  obtained  mono-toromoarsanilic  acid  toy 
the  direct  toromination  of  arsanilic  acid  with  half  the  theoretical 
amount  of  bromine, 

110  g,  of  arsanilic  acid,  mole)  was  dissolved  in 
2000  cc.  of  hot  glacial  acetic  acid  and  the  solution  quickly 
chilled  to  room  temperature,  A solution  of  40  g,  of  bromine 
(i  mole)  in  glacial  acetic  add  was  then  added  with  good  stirring 
during  the  course  of  4-5  hours.  The  product  was  isolated  accord- 
ing to  the  23rocedure  of  Bertheira,  and  the  monobromo  arsanilic  acid 
separated  in  white  leaflets  weighing  52  g.  or  70^  of  the  theor- 
etical amount.  The  yield  stated  by  Berthe im  was  47^  and  the  im- 
provement was  probably  due  to  the  very  slow  addition  of  the 

bromine,  good  stirring  and  the  use  of  a slightly  larger  amount  of 
solvent.  • 


■ ' f 


\ 


•*  J 


‘ t.  O t;  21  • ^ 


-’I.'tr  lil 


i . . ' ■ 


, r • 


. -ii.-  r.rf  if 

:.  ■ "•.lid  . '■'  *»a- 

f 

'1"  lo  • rr'X".:,ti’ 


•)%  j hefiido 


[i. 


.V'^  • A »•  V 


rrt;  7Jf<:"'V05t,f 


S7 

B,  The  Condensation  of  Arylsunino  Arsonic  Acids  with  Pyruvic  Acid 

and  Aldehydg3. 

41 

Arsanilic  Acld>  Pyruvic  Acid  and  Benzaldehyde:  A mixture  of  21.7 
g,  of  arsanilic  acid  (1  mole),  10,6  g.  of  benzaldehyde  (1  mole) 
and  300  cc.  of  absolute  alcohol  ^as  heatea  to  boiling  under  reflux 
on  a steam  bath.  After  a short  while  moat  of  the  arsanilic  acid 
passed  into  solution  and  8.8  g.  of  pyruvic  acid  (1  mole)  were 
added.  The  solution  was  then  heated  to  boiling  for  3-^-4  hours 
and  then  filtered  hot  to  remove  a slight  amount  of  insoluble  mater- 
ial. On  cooling  the  filtrate  a yellow  precipita-te  resulted  which 
was  filtered,  washed  sparingly  with  alcohol,  finally  with  ether 
and  then  dried  in  vacuo.  The  crude  condensation  product  thus  ob- 
tained was  pale  yellow  in  color  and  melted  with  complete  decomposi- 
tion at  130^-183°.  After  one  crystallization  from  ordinary  alcohol 
and  washing  with  alcohol  followed  by  ether,  the  substance  is  pure 
and  is  then  a cream  colored  powder  which  starts  to  darken  at 
about  180^,  and  melts  with  decomposition  at  183^-187°  (cor.)  The 
yields  of  crude  product  varied  from  18-34  g,  which  is  50-35^  of 
the  theoretical  amount.  After  repeated  crystallization  from 
alcohol  the  substance  was  obtained  in  pure  white  leaflets. 

The  arsenic  was  determined  by  Ewins*  method,  the 
nitrogen  by  the  Kjeldahl  method,  and  the  carbon  by  the  Parr  total 
carbon  method: 


Subs,  0.5001, 

0.5005 

g. , COg,  563.5  cc. 

565.3  cc. 

(28.5^, 

746  mm) 

(30.5^, 

746  mm) 

0.1999, 

0.2033 

g,  required  14.43, 

14,49  c 

c.  0.0736  N I 

0.5001, 

0,5034 

g,  18.33,  18.36  cc. 

0.0699 

N HCl. 

I 


I 


I 


i 


i' 


i 


I 


1 


’S:2aae 


• » » ^ • j - * ^1  A- 

.^  - J ,*f  . ‘.J  - 


' . r ’ . or  • ‘l 


Calc,  for  Cje^j^OgNAs:  C,  51.20fo;  As,  20.00fo;  N,  3,73;;. 

Found;  C,  51.54,  51.30foj  As,  19.97,  19.77foj  N,  3.58,  3.57f.. 
This  substance  is  slightly  soluble  in  water;  mors  soluble  in  cold 
methyl  and  ethyl  alcohol  and  glacial  acetic  acid,  very  soluble  in 
these  solvents  hot;  insoluble  in  ether  and  organic  solvents.  It 
is  re>adily  soluble  in  alkali  hydroxides  and  carbonates,  and  in 
ammonia;  insoluble  in  dilute  mineral  acids  in  the  cold,  decomposed 
on  warming. 

When  the  crude  material  was  recrystallized  from 
alcohol  a certain  amount  of  insoluble  material  remained,  which 
consisted  in  part  of  benzylidene  arsanilic  acid.  The  latter  was 
isolated  by  boiling  the  residue  with  a large  volume  of  absolute 
alcohol  and  allovving  the  filtrate  to  cool  and  concentrate.  The 
benzylidene  arsanilic^*  acid  separated  in  white  heavy  granular 
crystals,  readily  soluble  in  alkalies,  and  decomposing  on  heating 
to  235°. 

Subs.  0.2078,  0.2100  g.  required  15.27,  15.43  cc.  0.0893  N I. 

Calc,  for  C13H12C3HAS:  As,  24.5Sf5.  Found;  As,  34.S0fc,  24.82^. 
In  addition  to  the  benzylidene  arsanilic  acid  a less  soluble  sub- 
stance remained  in  the  insoluble  portion. 

A number  of  experiments  were  made  to  determine  the 
best  conditions  for  carrying  out  the  reaction  and  it  was  finally 
decided  that  the  use  of  mechanical  stirring  and  a temperature  of 
65^-70°  are  the  most  favorable  conditions.  It  was  found  that  only 
half  of  the  alcohol  was  essential  to  carry  out  the  reaction  and 
obtain  complete  solution  of  the  products,  but  the  mass  becomes  so 
solid  on  cooling  that  it  is  advisable  to  use  the  larger  quantity. 


\ 


} 


• w* 


..3 


I '■•C- 


••  r,  a*-a(rrwi«»-iiB 


S9 


It  was  found  that  ethyl  alcohol  could  he  replaced  by  methyl,  and 
the  condensation  effected  in  the  usual  mannei^^  . It  is  unneces- 
sary to  use  absolute  alcohol  for  the  solvent,  and  fair  results 
were  obtained  by  the  use  of  95^  and  90fo  alcohol.  In  these  cases, 
however,  the  yields  were  not  so  good  and  the  product  was  more 
highly  colored. 

The  saiue  product  resulted  from  the  use  of  ethyl 

34 

pyruvate  instead  of  pyruvic  acid,  under  the  same  conditions. 

11.6  g.  of  ethyl  pyruvate  ms  substituted  for  8.8  g,  of  pyruvic 
acid  in  the  above  directions.  The  product  was  isolated  in  the 
usual  manner  but  the  yield  was  poorer  than  when  pyruvic  acid  was 
used.  The  product  after  recrystallization  from  absolute  alcohol 
melted  from  1S5°-187®,  w.  dec.,  and  a mixed  melting  point  with  the 
first  condensation  product  was  not  lowered. 

Subs.  0,3074  g.  required  1^.42  cc.  of  0,0893  N I. 

Calc,  for  CieHi405Ms:  As  * 30.00^.  Found:  20,06^. 

The  condensation  ms  also  carried  out  in  ether,  but 
in  this  case  the  reaction  was  incomplete,  due  to  the  insolubility 
of  the  arsanilic  acid.  A mixture  of  10.6  g.  of  benzaldehyde  and 
8.5  g.  of  pyruvic  acid  was  added  to  21.7  g.  of  arsanilic  acid 
covered  with  350  cc.  of  ether.  The  mixture  was  stirred  vigorously 
for  40  ho'urs  and  at  the  end  of  this  time  a flocculent  precipitate 
had  formed  in  the  ether.  This  was  sepsxated  by  decantation  from 
the  heavy  granular  crystals  of  unused  arsanilic  acid  and  then 
filtered  from  the  ether.  The  material  weighed  20  g.  and  was  much 
darker  yellow  in  color  than  the  ordinary  crude  condensation 
product.  After  two  crystallizations  frcm  alcohol  the  material 
was  obtained  in  white  leaflets,  ra.p.  185^-187°,  w,  dec,  and  was 


A 


t 

I 


I 

;r 


r 


I 


) 


I 


vK-  ^ 


I 


» 


:ro':;iL  c 

Xf  Xv  . '. -..i  -Tv-. 

• ^ -^.  •' 0‘iiu 

.-"  * ■ -'  •-  -i 

't* 


I , 

I 


k 

I 

1} 

il 


if 


I 

) t 


■ I 

I 

II 


I 

H 


’■I 

i 


.•  .wi 


30 

proved  to  ’00  identical  with  the  first  condensation  product  by 
mixed  melting  points  and  analysis: 

Subs.  0,1516  g.  required  9.10  oc,  of  0.0893  N I. 

Calc,  for  C1GH14O5NAS:  As,  20.00^.  Found:  30. 10*^. 

The  reaction  between  arsanilic  acid,  pyruvic  acid  and  substituted 
aldehydes  was  carried  out  according  to  the  directions  given  for 
benzaldehyde,  using  each  one  of  the  constituents  in  equimolar 
proportions. 

Sal ioyl aldehyde : This  aldehyde  gave  an  orange  red  solution  from 
which  a product  separated  on  concentration.  This  was  more  highly 
colored  than  that  from  benzaldehyde,  and  it  rapidly  darkened  on 
exposure  to  the  air.  No  suitable  method  of  purification  was  found. 

3~Methoxy  benzaldehyde:  Using  the  methyl  ether^®  of  salicyl  alde- 
hyde instead  of  the  free  phenol,  a good  yield  of  the  condensation 
product  was  obtained.  The  material  after  crystallization  from 
alcohol,  was  obtained  as  a pale  yellow  powder,  m.p.  173^-176°, w. dec. 
Subs.  0.2025,  0.2032  required  12.61,  12.25  cc.  0.0808  N I. 

Calc,  for  0 As,  18.5Sf.,  Found:  18.87fc,  18.36^'. 

4-Methoxy  benzaldehyde : Aniaaldehyde  gave  a product  which  after 
crystallization  from  alcohol  was  almost  white;  m.p,  164^-165^, w, dec. 
Subs.  0.2005,  0,2000  g,  required  10.38,  10,51  cc.  0,0954  N I. 
Calc,  for  Ci^HisOgNAs:  As,  18.56^^,  Found:  18. 53-^.,  18.63f^. 

4-Dimethylamino  benzaldehyde:  When  the  pyruvic  acid  was  added  to 

3 6 

a mixture  of  arsanilic  acid  and  dimethylaraino  benzaldehyde  , a 
deep  red  color  was  formed  which  became  darker  during  the  heating. 


** 


t 


i 

I 

j 

I 

! 


i 


c 


31 

The  product  separated  as  a dark  red  powder,  which  was  purified 
with  difficulty  from  alcohol. 

5. 4~Methyl9nedloxy  henzaldehydei  Piper onal  was  found  to  give  a 
good  yield  of  the  condensation  product,  which  after  crystalliza- 
tion from  alcohol  was  obtained  as  a light  yellow  powder,  m.p, 
176^-178°  w.  dec. 

Subs.  0,1474  g.  required  7,80  cc.  0.0893  N I. 

Calc,  for  Ci^^i^O^NAs:  As,  17.S0fr.  Found:  l?.73^c>. 

4-Chlorobenzaldehyde  : This  aldehyde  gave  satisfactory  yields  of 
a product  which  after  two  crystallizations  from  alcohol  was  ob- 
tained as  a white  powder,  m.p,  133°-165^,  w.  dec. 

Subs,  0,3505  g,  required  14,90  cc.  of  0,0808  N I. 

Calc,  for  Cl eHiaOsNClAs:  As,  18,39^.  Found:  18.0Cf/c. 

Cinnamic  Aldehyde:  This  aldehyde  seemed  to  react  with  the  arsan- 
ilic  acid  and  pyruvic  acid,  but  only  a colored  impure  condensation 
product  was  obtained,  and  no  method  was  found  for  its  purification. 

Paraldehyde : In  place  of  103  g.  of  benzaldehyde,  4,4  g.  of  paralde- 
hyde was  used  and  in  this  case  no  condensation  product  separated 
from  the  cooled  solution.  On  allowing  ^ of  the  alcohol  to  evapor- 
ate, 18  g.  of  a yellow  solid  remained,  A portion  of  this  was 
crystallized  from  ''vater  and  proved  to  be  impure  arsanilic  acid: 
Subs.  0.2001,  0.1996  g.  required  24.50,  24.13  cc.  0.0736  N I. 
Calc,  for  CiiHigOsNAs:  As,  23,96/('.  Found: 

C17H10O7N3A33:  As,  29.30^4  33.79 

Arsanilic  Acid:  34.56fo  33.  35f. 


33 

n~Butyr aldehyde  was  also  tried,  but  no  condensation  product  was 
obtained. 

8~Aminophenyl  Arsenic  Acid.  Pyruvic  Acid  and  Benzaldehyde ; In  con- 
trast to  the  p-compound,  o-arsanilic  acid  is  quite  soluble  in 
alcohol.  To  carry  out  the  reaction  the  o-arsanilic  acid  ivas  dis- 
solved in  the  liot  alcohol,  and  the  benzaldehyde  and  pyruvic  acid 
added  to  the  hot  solution,  A crystalline  precipitate  was  formed, 
but  on  heating  for  1-1-j  hours  at  70^  this  redissolved.  On  filter- 
ing and  cooling  the  reaction  mixture  to  20°  no  precipitate  formed, 
but  on  concentrating  and  cooling  to  -10°  a yellow  precipitate 
resulted.  This  was  analysed  and  found  to  be  the  benzylidene  deri- 
vative of  o-arsanilic  acid,  m.p.  227°-339°. 

From  a simils.r  experiment  the  crystalline  precipitate 
obtained  at  first  was  filtered  and  washed  with  alcohol  and  ether. 

It  is  a heavy  granular  material,  m.p.  826°-228°,  with  previous 
darkening.  Analysis  indicated  that  it  was  benzylidene  o-arsanilic 
acid,  CeHBCH-N.CeH^.AsOaH^: 

Subs,  0.1997  Tequired  14.70  cc,  0.0893  II  I. 

Calc,  for  CisHisOsNAs:  As,  24.58fc.  Found:  24.66f.. 

The  filtrate  from  the  crystalline  precipitate  on  cooling  deposited 
an  additional  amount  of  material,  almost  white  in  color.  This  was 
filtered,  washed  with  alcohol  and  ether,  and  found  to  melt  from 
325^-228®.  This  indicated  that  it  was  benzylidene  o-arsanilic 
acid,  and  was  confirmed  by  analysis: 

Subs.  0.1985  g,  required  14,63  cc.  0.0893  N I. 

Calc,  for  CisHjgOsN  As:  24.58^4,  Found:  24,74fo, 


33 

For  comparison  a sample  of  benzylidene  o-arsanilic  acid  was  pre- 
pared by  heating  o-arsanilic  acid  with  one  mole  of  benzaldehyde 
in  alcoholic  solution.  The  product  crystallized  out  in  granules, 
m.p,  288^-330®,  and  was  identical  with  the  above  compounds, 

3- Methyl~4-Aminophenyl  Ar sonic  Acid,  Pyruvic  Acid  and  Benzaldehyde: 
Methyl  arsanilic  acid  was  treated  with  benzaldehyde  and  pyruvic 
acid  in  the  usual  way  and  no  condensation  product  separated.  On 
evaporating  ^ of  the  alcohol  and  cooling,  a product  separated 
which  was  filtered  and  washed  with  alcohol  and  ether.  This  was 
recrystallized  from  alcohol  and  obtained  as  a cream  colored 
powder,  m.p.  202°-305®,  w,  dec.  The  analysis  indicated  that  it 
was  the  benzylidene  derivative: 

Subs.  0,2001,  0,2000  g,  required  13,80,  13,90  cc. 0.0893  N I. 
Calc,  for  Ci4Hi403WAs:  As,  23.5lf^.  Found:  33.  lOf^,  23.38fo. 

The  reaction  was  repeated  wixh  longer  heating,  but  the  same 
product  was  obtained, 

4- Chlorobenzaldehyde : Using  p-chlorobenzaldehyde  in  place  of  bena- 
aldehyde,  a yellow  precipitate  was  obtained  from  the  reaction 
mixture  on  cooling.  This  was  crystallized  frora  alcohol  and  ob- 
tained as  a pale  yellow  po^wier,  m.p,  355^-260®,  w,  dec.  The 
analysis  indicated  that  this  was  the  benzylidene  derivative  and 
that  the  pyruvic  acid  had  not  taken  part  in  the  condensation: 

Subs.  0,2018,  0,2001  required  13.74,  13,31  cc.  0,0803  TT  I, 

Calc,  for  Ci^HigOgNClAs:  As,  31,20fo. 

2-Nit robenz aldehyde : From  this  reaction  a product  was  obtained 


-r»ia-i:«rSlCS^ 


34 

which  was  purified  with  difficulty  from  alcohol.  Analysis  in- 
dicated that  it  was  a mixture  of  arsanilic  acid,  and  a small  amount 
of  other  material: 

pubs.  0,3003  g.  required  17.98  cc,  0.0893  N I, 

Calc,  for  arsanilic  acid.  As  34.56a'«  Foiond:  30,1^. 

3-3romo-4-Aminophenyl  Ar sonic  Acid.  Pyruvic  Acid  and  Benzaldehyde : 
When  bromo-arsanilic  acid  was  used  in  place  of  arsanilic  acid  it 
was  very  difficult  to  isolate  any  product  from  the  reaction  mixture. 
On  concentrating  to  a small  volume,  a precipitate  was  obtained  which 
was  purified  with  difficulty  from  alcohol.  This  substance  proved 
to  be  chiefly  unchanged  bromo-arsanilic  acid,  probably  contaminated 
with  some  of  the  benzylidene  derivative: 

Subs,  0,3334  g.  required  16.07  cc.  0.0393  N I 
Calc,  for  Bromoarsanilic  acid.  As,  35.335^. 

Benzylidene  derivative.  As,  19.53';^ 

Found:  As,  33.16f5. 

2- Methyl-4-Aminophenyl  Arsenic  Acid.  Pyruvic  Acid  and  Benzaldehyde : 

A suspension  of  the  ar sonic  acid  in  absolute  alcohol  was  treated 
with  benzaldehyde  and  pyruvic  acid,  and  vigorously  stirred  under 
reflux  at  70°.  The  acid  gradually  passed  into  solution  and  after 

3- 3^  hours  heating  the  reaction  mixture  was  filtered  and  cooled. 

The  condensation  product  separated  in  good  yield  and  after  washing 
with  alcohol  and  ether  remained  as  a cream  colored  powder  decompos- 
ing on  heating  from  130°-186°. 

Subs,  0.1981,  0,2003  g,  required  11.33,  11,55  cc.  0.0893  N I, 
Calc,  for  Ci7Hi60b^As:  As,  19.37^.  Found:  19.14'^,  19.27/c, 


■V 


35 

3~M3thoxy~4~Aminophenyl  Arsonic  Acid.  Pyruvic  Acid  and  Eenzaldehyde : 
Using  the  same  method  as  in  the  preceding  example,  the  condensa- 
tion product  was  obtained  as  a yellow  powder  decomposing  on  heating 
to  175°-130°,  with  previous  darkening. 

Subs.  0.1472  g.  required  7.79  cc.  0.0893  N I. 

Calc,  for  Ci^HieOsNAs:  As,  18.56fo.  Found;  17.73^9, 

Condensation  of  an  Aminoaryl  Arsinic  Acid:  An  arsinic  acid  derived 
from  p-arsanilic  acid  was  available  and  this  was  treated  with 
pyruvic  acid  and  benzaldehyde  in  the  usual  manner.  From  p-amino- 
phenyl  arsinic  (acid)  acetanilide’,  p-NHsCeH^AsOgH.  CHgCOITHCeHs,  a 
yellow  solid  was  obtained  decomposing  at  173°-175°. 

C.  Reactions  of  the  Condensation  Products. 

For  studying  the  structure  of  the  condensation  products- 
the  substance  was  used  that  was  obtained  by  heating  p-arsanilio 
acid,  benzaldehyde  and  pyruvic  acid  in  absolute  alcoholic  solution. 
The  material  was  recrystallized  from  alcohol  and  was  obtained  as  a 
cream  colored  powder  melting  with  decomposition  from  185°-187^, 
with  previous  darkening. 

Decomposition  on  Heating;  A qualitative  experiment  showed  that  the 
material  evolved  carbon  dioxide  on  heating  to  its  decomposition 
temperature,  and  in  order  to  obtain  definite  information  the  ex- 
periment was  carried  out  quantitatively.  A weighed  sample  was 
suspended  in  ethyl  benzoate,  heated  to  boiling  for  20  minutes,  and 
the  carbon  dioxide  in  the  gas  evolved  was  determined  by  difference 
after  absorption  in  potassium  hydroxide. 

Prepared  by  the  action  of  ohIoroacotanMtde  upon 
sodium  phenyl  arsenlte,  Peferonoe  58. 


f 


li 

It 


I 

i 


I 


■0^  ..ii  ■ I 

’ . ' 1 

y 


:r:,  ^ 


I,  ,<.  J • 


t.' 


. . . • t.  • V . 


v,l  ' ■ ' •'  ri 

t.i 


■f  . •• 


. -Jt\ 


Subs,  1,000  g,  gave  53,5  cc.  COg,  24°  and  743  mm. 


Converted  to  standard  conditions  5S.3  cc. 

Calculated  for  one  mole  COg 60,0  cc. 


These  date  indicated  that  the  amount  of  carbon  dioxide  formed 
corresponded  roughly  to  one  mole. 

This  reaction  was  first  considered  to  be  evidence  of 
the  cinchoninic  acid  formula  for  the  product,  but  in  order  to  be 
sure  of  the  conclusion  it  was  decided  to  try  an  experiment  with  a 
known  diketopyrrolidine , For  this  purpose  the  compound  prepared  by 
Borsohe^®  from  p-nit rani line,  pyruvic  acid  and  benzaldehyde  in  al- 
coholic solution  was  used.  On  repeating  Borsche’s  work  the  com- 
pound was  obtained  as  a yellow  powder,  ra.p.  182°-183°,  after  re- 
peated crystallization  from  glacia.1  acetic  acid. 

The  decomposition  was  carried  out  exactly  as  in  the 
preceding  case; 

Subs,  1.042  g.  gave  54.2  cc.  COg,  25®  and  755  mm. 


Converted  to  standard  conditions  49.3  cc. 

Calculated  for  one  mole  COg 78,8  cc. 

Found;  of  one  mole. 


Since  it  was  thought  that  the  presence  of  an  arsonic  acid  grouping 
might  affect  the  decomposition,  a similar  experiment  •'^^s  carried 
out  in  which  2 g.  of  o-nitrophenyl  arsonic  acid  was  ad.ded  to  the 
material  'oaf ore  heating. 

Subs.  1,118  g.  gave  89,4  cc.  COs,  38®  and  755  ram. 


Converted  to  standard  conditions  80,7  cc. 

Calculated  for  one  mole  COs 84.7  cc. 

Found;  95fo  of  one  mole. 


• ^ 


37 


These  results  were  altogether  unexpected  since  it  is  not  easy  to 
explain  the  formation  of  a mole  of  carbon  dioxide  on  the  decomposi- 
tion of  a diketopyrrolidine  derivative, 

COgH  / \ ,CO-CO 


H gO  3 As 


N; 


eHj 


CH-CHg 

CeHs 

II 


This  indicated  that  the  formation  of  carbon  dioxide  on  decomposing 
the  condensation  product  could  not  be  taken  as  evidence  for  dis- 
tinguishing between  these  formulae,  providing  the  compound  ob- 
tained from  p-nitraniline  is  a true  diketopyrrolidine  derivative, 
as  it  is  formulated  by  Borsche  to  be. 

On  boiling  the  condensation  product  with  mineral  acids, 
a heavy  viscous  oil  is  formed  which  sinks  to  the  bottom  of  the 
container  and  on  cooling  sets  to  a brittle  mass.  An  attempt  was 
made  to  esterify  the  substance  by  treating  with  dry  hydrochloric 
acid  in  alcoholic  solution,  but  the  acid  caused  decomposition  of 
the  condensation  product. 


Fusion  with  sodium  hydroxide:  The  fusion  of  phenyl  arsonic  acid 
with  alkalies  was  carried  out  by  La  Coste  who  states  that  it 
gives  with  potassiuin  hydroxide  ^ phenol  and  benzene,  but  with 
sodium  hydroxide  chiefly  benzene.  It  thus  appeared  that  by  fusion 
of  the  condensation  product  with  sodium  hydroxide  an  arsenic  free 
substance  would  be  obtained  that  could  easily  be  identified.  To 
test  out  the  reaction  two  preliminary  experiments  were  run: 

a..  25  g.  of  phenyl  arsonic  acid  was  mixed  thoroughly 
with  five  times  its  weight  of  sodium  hydroxide  and  distilled  from 


JW  w - 


» 


' t • 


L‘  t.'?  iV  t 


1.;' 


^ • .V, 


“i  rf 


’ ■>i 


. I 


' fr  ' 


— TK 


'.'f  11 

\J. 

r v * 5i5=»Ed;:9aaEi  ..: 


r;,  *'ts';.\Ow i>.  fcl&> 

• Vo  ^ -Vi  rttsldxo 


* ^ r 


t*  • — 


. ' V i * ■ V i J t iO«5Vtf  :>J^i  It*  flO.^ 


'.  *>A 


•lol  t 

iv*  sui^o*^-,  eiJr 

■ '•  * > 

<5‘ 

, • ■ _ tic,:  ^ f r 

' •i.  ' ' ® 


"i>‘- 


V 'IS  ,;• 

- 'v  I'  ■'  ' J.  i *lO^^>|j  *'■*»  * 

^ r •.  "K’ 


.1  '•/••* 


. - la-i 

V ■•••jr 

?•  i 


■ i»os>Xv  vtilbgr^ 

=;.x< 


■'M.:  rov  oiiDrfQviB-ai,ii>iOie„ 


-4  ^ -'■•lafe* 


; .'  :.i^i  aexei;^ 

, : v'^  :/ : ■ : r>  ‘ » a ' _ 

59  ~ wJI^VAi 


* " . • M 

‘ ^ . = -_  ASi  .1 


.:;>  5J 


V r ' 0 t i*  X/  ■ T f i4i/.f  iioft 


, „ , . ..  :.v  ioiij  c'xr^  gv* Vo 


■ ! 'll 'I'- ,*?'  *'j3oi«t  Ca-ic'  oTt»  , 

. , 'J»='tj.‘  '■■  J ■ ■ ' < 


V*  i 


■ . ■ » I 


-iV:?.i»  *.•  A i.  Xf;.c  0 tT . tt is"  i wt » tq.  J«,.  .’*"■ 


"T  "T'  ••gyrr^^’saaa;^^  ,ijf  ^frayin 


3 3 

ammonium  salt  may  toe  prepared.  The  toehavior  on  treating  with 
sodium  hydroxide  is  rather  unusual: 

The  material  dissolved  readily  in  one  mole  of  aqueous 
sodium  hydroxide  to  a clear  yellow  solution  which  was  filtered  and 
allowed  to  stand  at  room  temperature.  After  a short  while  the 
solution  toecame  turtoid,  and  deposited  a white  precipitate.  A 
strong  odor  of  toenzaldehyde  was  noticed.  After  24  hours  the  pre- 
cipitate was  filtered  and  examined.  It  contained  arsenic  and  was 
solutole  in  alkalies;  it  was  purified  with  difficulty  from  alcohol 
and  obtained  as  a white  poiivder  melting  with  decomposition  from 
140^-150°. 

On  treating  the  condensation  product  with  two  or  more 
moles  of  sodium  hydroxide  a clear  yellow  solution  resulted  which 
remained  perfectly  clear  for  an  indefinite  period,  A few  tests 
were  made  to  determine  in  a rough  way  the  Pjj  values  of  solutions 
of  the  condensation  product  in  various  quantities  of  alkali.  The 
Clark-Lutos  series  of  indicators  was  used: 


Sodium  Hydroxide 

value 

Notes 

a,  1 mole 

approx  3,0 

deposits  white  precipitate 

D.  1-^  moles 

3,5  - 4.4 

deposits  white  precipitate 
not  as  much  as  in  a. 

c,  2 moles 

7,2  - 8.0 

clear  yellow  solution 

d,  2i  moles 

approx  8.8 

clear  yellow  solution 

e.  3 moles 

8.8  - 9.6 

solution  darker  than  c. 

From  a solution  of  the  condensation  product  in  two 
moles  of  alkali,  copper  sulfate  precipitates  a green  salt;  silver, 
lead,  mercurous,  mercuric,  cadmium  nitrates  light  yellow  salts  and 
cotoalt  and  ferric  nitrates  red-torown  salts. 


mi 


Vf> 


Hft 


; . ^ ..  jVltiS}  t'  -fl  1 - p^  L^ch,t^{LMUtt^9 


’ : I.'  r 't:  i/' 


h w-roiJK'-tXk' *''^  7 


<5J?  hryrtfj^y  •!)&?. 


■*I  ' v«-i»n 

- , f,  fif;-.”  ^h^KlTJSJ  nolfuSot, 


1 If  ► *1 


^ ‘ ' 


41 W (?  I l4 ?>1LX if  ^ 

■ .^  V,‘V. ' 


i'  ■ .'  * ' I j Lt  - * ; f ■*:  iij  •—i’  r.I.  •XcjyrXot* 

■•  ' .n  ..,;£>-u  ''  iM,.  •■  f/iiiiK  i r 

' I -i 


si' 


■ 


f-  -.ii 


t r \ 

V^ 


X I I 


't'  *A  •'» 


t y !. 


tjf  t.'i'  -■  _ K 


/ ?iui:h6t,  \o  ‘e^oW 

ir*  ^,i'i,:£Vi  ' : c r:/'  "i  .'l 

, ' j * . fTi*, 

jry  ,Jfi  -•  A a snir ftTvifr 

, . .•*,  - Lfr:  r-LOl*iff-  '-  jiouw  :q  noX^r»ano|ifCit>  ufC? 


i '? 


(i  i/ .. -‘■MtnqNf 


: ,r  M t>v/.  .,tv  ' r *ijri  5o 


»:• 


* .=  j;“ij 

.’^'.ry  ' l'‘  ?Oii 


* - r 

"v,.'  . 


'4 


' / - ^ £o 


/;  .4'^  * .V  "i  C‘XO 


ri.S.,H  . 


C.9  - \ .A  c<^0| Y S ^ ,»-j 

- ■ _.''Ji  -'^1;<'  . Bl 

8.6 

■ -ii  . V > ' ‘ W i/, 

l.' '.}'i.i‘'T=’{  HP  vv' PC>».  il  £'olOB  ,v;\i(| 

^ ^ ■ ' '•  • ■ ' 1 ' y'  ' M 

iT . >a,.  i*  |<§  iei6«'' 

• ;;..  i-V  /*'\;aX  R?/;rA5'2;tXwf  «iu.-'io|^V 


£>  I 


iM). 

TCS.ver^CSXSSirj:^  Trf3^iis?.:;J3B«fc'5CBlj(^^ 


3B 


a copper  flask.  From  the  distillate  there  was  obtained  5 g,  of 
benzene,  water  and  a small  amount  of  a crystalline  substance, 
presumably  diphenyl. 

b,  35  g,  of  arsanilic  acid  was  fused  with  sodium 
hydroxide  under  the  same  conditions  and  gave  7 g,  of  aniline, 

c,  30  g,  of  the  condensation  product  on  fusion  with 
150  g,  of  sodium  hydroxide  gave  a distillate  which  consisted  of  a 
red  oily  substance  and  water.  This  was  treated  as  indicated: 

Acidiftad  with  dilute  hydrochloric 
acid  and  extracted  with  ether: 

§ther_Extr§£t;  ii^^3:®£]jl£EiS._££i5_§5i£3£i* 


Oried  over  calcium 
clori  demand  thee 
distilled: 

a.  2-5  cc.b.p.120-150® 
probably  phenyl 
ethylene. 


Treated  with  sodium 
a red-brown  oi  Intake 
dried  and  distilled: 
a.  4-5  cc. 175-185° 
identified  as  anil- 
ine,by  conversion 
to  acetanllid. 


hydrox  ide  ,gave 
n up  in  ether. 


b.  few  drops 
a very  hish-botl 
ing  base, which 
decomposes  on 
distillingl. 


The  formation  of  aniline  from  the  condensation  product  indicated 
that  it  was  not  the  phenyl  cinchoninic  acid  derivative  , since 
this  would  yield  phenyl  quinoline,  but  it  does  not  help  to  distin- 


guish between  the  formulae  II  and  V: 


HgOs As 


>N^ 


CO-CO 


H 3O3 As 


CK-CKs 

CsHs 


>1^=C-C0. 

I > 

H3C-CH 

CgHs 


II.  V. 

Tres.tment  with  aqueous  alkalies:  The  condensation  product  is 
readily  soluble  in  caustic  alkalies,  carbonates,  and  ammonia.  By 
passing  dry  ammonia  into  a solution  in  absolute  alcohol,  a mono- 


1; 


- ^ 'iT  cT?  V - ♦ ‘ '. *' 

’ ' • * . ■ ' ' ■’  . , * «■ 

‘ ;,r.  i.'  ■.  'c-r  *-  * ^‘'’ 


' X',.v*  «snDi-#iii  f tiSki  vr.:i 


■’.  :•  . *.  i 


J .,1.*  - 


<rji!  i'-OTi'iffr  r 


\at‘>  Cs4 


^ * 


» I * « r '.  . ^ 1 tt  ^ » > ) I ' • i.'i  f I - * f ♦ I I » ' 
<»..,.*  t M * A » » * » « r * ♦ • ' » M * 


/ » 3 ^ I f v(  . f ' 1 1 1 i M ? I ♦ ^ 


I «l 


% ♦ “ 
» • e 

9 » |T 
« . 


w i t « 

) if  f -I  ■ « 

, « .)  I ’ 

« I t • 4 <>  V 

1 I I M f • i * 


f ■»  .ii 

) , , I • , • n »•  t i » - ,-  V • ’ 

. ( I i » V *•  » » I ( • 

, ' • t . " - • <► 

.,((••  » * • * I • L » ‘ - t 

,\  ..  t . t 1 # t I '.'  , » '*■  f 

, > I I • « » » 4 * ' 


•tJ.  i U;  .H  ill  4 

I ■ ■»#*<»  * * ^ 


*7  ^■•  ' ’*  A.f 


:;f  ■ 'fA' ■ 


f4  V.'  <sV*'Vv'4 

.vCfv'’l  •»**'»>  rf-i  « j 

'"  -jAi  ,'i|S 


■ >f*!_ 


f ','  .'  ' 'J  4 . ’ 


If.-  raf.'fi?  f I lfT»  ^ 

* ^ ^ ida£  h 


.ft’ 


n: 


-7 


.- •:  fl-:  :'  .scfi 'TM  ' :..  i f ‘' ■ ' ] 

.:'’  t,rj  ir  i'-,' :u..7x^^  H 

^ -■'^  'fid  ' 

•.  -''  ,■'?  ■■•  • I '...:(!:  v.|^EAcO.K 

ri-  . 


( ^ # I 


W^H  T.  V 

, 1 ■'  ;‘;,;Mi  ’'•■■  ‘JTt-r, '"’f  i . : -'^J 

■"  ' ' ',7^“ 

...!..»{4.<*  cyr/roeC'f  fll  <r.>x^tr.rc»6 

»i , * t *fii.  1 I il ' 


L 


»i 

. f 


»'  tiff' 3:'ifatgJMe  ,S.'Vitfiwy45t.?i^ J.'WStf-y *»  -•»•« 

*1 


40 

An  attempt  wa-s  made  to  isolate  a sodium  salt  by  pour- 
ing an  aqueous  solution  of  the  mono-sodium  salt  into  absolute 
alcohol.  A white  precipitate  resulted  which  was  filtered  and 
washed  with  dry  ether.  An  analysis  indicated  that  this  was  the 
di-sodium  salt  of  arsanilic  acid: 

Subs.  0.1830,  0.3105  required  15.36,  17.70  cc.  0.0893  N I. 

Calc,  for  CsHeOgNAsNag : As,  28,73^-.  Found:  38.07^,  SB.lTf;. 

This  salt  forms  very  hygroscopic  white  crystals  which  dissolve 
readily  in  water  to  a clear  solution.  It  does  not  appear  to  have 
been  described  in  the  literature. 

Treatment  with  aniline:  With  the  ilea  of  obtaining  an  anil  from  the 
4-keto  group  in  the  formula  II,  a solution  of  19  g.  (l  mole)  of  the 
condensation  product  in  100  cc.  of  hot  absolute  alcohol  was  treated 
with  4.5  g.  (1  mole)  of  aniline.  The  solution  turned  red  in  color 
and  was  heated  for  -l—J  hour.  On  cooling  a precipitate  formed  which 
was  filtered,  washed  with  ether  and  examined.  It  was  found  that  a 
considerable  portion  of  the  material  was  insoluble  in  boiling  10^ 
sodium  hydroxide,  and  therefore  did  not  contain  the  arsonic  acid 
groupirig-.  This  material  was  filtered  and  investigated.  It  melted 
with  decomposition  from  147^-148®  and  was  thought  to  be  identical 
with  the  compound  ra.p,  147®-148°  obtained  by  Schiff®^  and  by 
Garzarolli-Thumlackh’-’’'on  treating  benzylidene  aniline  in  benzene 
solution  with  pyruvic  acid. 

It  was  thought  that  by  treating  the  condensation 
product  with  an  excess  of  aniline,  the  Dfibner  anil  compound,  rn.p, 
335®  could  be  obtained,  and  an  experiment  was  carried  out  as  above 
using  3-5  moles  of  aniline.  On  concentrating  and  cooling  a precipi- 


!' 

II 

i: 

M 


i 

: < ...  ■ 1..  ’ ;i 


i 


iKi  •;:I  aci/.ti.-  i| 


..  ».  ^ 


r»  ^ • V • 


!i 


41 


tats  was  obtained  which  was  completely  soluble  in  cold  soditan 
hydroxide.  On  neutralizing  the  filtered  alkaline  solution,  a 
precipitate  was  obtained  which  proved  to  be  arsanilic  acid.  None 


The  regeneration  of  arsanilic  acid  on  treatment  with 
such  a mild  reagent  as  aniline  seems  to  give  evidence  that  formula 
V is  more  likely  than  II.  Using  formula  V the  reactions  of  the 
condensation  product  can  be  explained  according  to  the  following 
diagram : 


of  the  compound  melting  at  325®  could  be  isolated 


n 


NHs 


CH=CH2 


+ 


CeHs 


+ CeHs-NC^HsOs-CsKs 
ra.p.l47°-148° 


A8O3H2 


CHsCH-OH-CeHs 


O 


1^2  + CO 


CH2CH*0H-C6Hb 


C02H 


CH3COC02H 


CgHs-  CHO 


+ 


H 2O  3 As< 


, V 

? 'ii? ' 

I 


t 


„■  ne.  .l<vr  vi;  /r  > ft  :v  '-'  ' 

l^,:  ■'  i-p.^;  .'  • C'  t^'*r:3:rjf  -’rn/.fifl.  tf&i’’ 

. . •,  ' . V'j^r  ,“j.<ii  .r'Hf 


\ I .' 


42 


IV.  STM  ARY 

The  application  of  the  DSbner  cinchoninic  acid  syn- 
thesis to  arsanilic  acid,  benzaldehyde,  and  pyruvic  acid  gave  a 
condensation  product  of  the  composition:  Qi  6H14.O5  NAs. 

The  reactions  of  this  condensation  product  were  studied 
and  the  follo'/Ving  formulae  proposed: 


The  structure  of  the  product  ms  not  definitely  established,  but 
the  evidence  favors  formula  II, 

By  the  use  of  various  aldehydes  and  aminoaryl  ar sonic 
acids,  the  following  generalizations  were  made  concerning  the 

limitations  of  this  reaction: 

i.  Aminoaryl  arsonic  acids  with  substituents  in  the 
ortho  position  to  the  aadno  group  form  benzylidene  derivatives 
which  do  not  react  further  \vith  pyruvic  acid. 

ii.  The  usual  condensation  products  are  obtained 
from  compounds  substituted  in  the  met  a position  to  the 
amino  group. 

iii.  The  reaction  is  general  for  aromatic  alde- 
hydes, but  not  for  the  simple  aliphatic  aldehydes. 


r/f.  :A.t  Ir  <0i  »'4Tf 


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43 


V.  BI3LlOGRj!|PHY 

1,  Frl^kel  and  L5wy,  Ber.  2546  (1913)« 

3.  Boehringer  and  SShne,  D.R.P,  240,793.  Frdl.  1252. 

3.  Miohaells  and  others,  Ann.  241  (1893);  330.  318  (1902). 

, Mroczkowski,  Diss.  1910,  - Berthe im ' s HandlDuch,  58,  108. 

Poulenc  and  Oechslin,  Fr,  Pat.  450,214;  462,  276;  473,704. 
Morgan’s  "Organic  Compounds  of  Arsenic",  166-7. 

4.  Michaelis,  Ann.  321.  141-248  (1902);  Pope  and  Turner,  J.  Chem. 

Soc.  177,  1447  (1930). 

5.  Bart,  D.R.P.  250,264.  Frdl.  1^,  1254;  cf.  D.R.P.  366,944  and 


237,307.  Frdl.  n,  1033. 

6.  Meyer,  Ber.  1440  (1883);  Klinger  and  Kreutz,  Ann.  249. 

147  (1388);  Auger,  Co^iipt.  rend.  137.  935  (1903);  Quick  and 
Adams,  loc.  cit. 

7.  Skraup,  M.  1,  316  (1330),  3,  139  (1831);  Kneuppel,  Ber. 

703  (1893);  Barnett,  Chem,  News  121.  205  (1920). 

8.  Knorr,  Ann.  333.  70  (1886);  Swins,  J.  Chem.  Soc.  103.  108  (1913) 

9.  Kulisch,  M.  15,  373  (1894). 

10.  DS’oner  and  v. Miller,  Ber.  lA,  2812  (1831);  13,  136  4,  3465 

(1883);  ]^,  1398  (1884);  2259,  3484  (1890);  Decker  and 

Remfry,  38,  3775  (1905);  Bartow  and  McCollum,  J,  Am.  Chem. 
Soc.  704  (1904);  note,  43,  2257  (1921);  Mills,  Harris 
and  Lamhourne,  J.  Chem.  Soc.  119.  1294  (1921). 

11.  Dobner,  Ann.  .242.  265  (1387);  249.  98  (1388);  m,  i (1894). 

12.  Friedl^nder,  Ber.  ,2574  (1833);  16,  1833  (1883);  25,  1753 


/ 


(1393) . 


i 

I 

I 

! 


I 

) 


I 


44 

13.  Pfitzinger,  J.  prakt.  chea,  (3)  283  (1897);  66,  233  (1902); 

Mulert,  Ber.  1904  (1903);  Ornstein,  Ber.  40,  1083  (1907). 

14.  Hubner,  Bar.  432  (1908);  Borsohe,  Ber.  354  (1914). 

15.  Schmidt,  Ann.  421.  168  (1931). 

IS.  Borsche,  Ber.  3884  (1908);  Ber.  4073  (1909). 

17.  Garzarolli-Thurnlackh,  M.  483  (1899);  Ber.  2274  (1899). 
13.  D.R.P.  394,159,  (1914);  C.A.  11,  2581  (1917). 

19.  Sharing,  Brit.  Pat.  15,481  (1913).  C.A.  9,  127  (1915). 

20.  Dobner,  Ber.  2030  (1894). 

21.  Schiff  and  Gigli,  Ber.  1310  (1898). 

22.  Jacobs,  Heidelberger  and  Rolf,  J. Am. Chem.  Soc. 40,  1580  (1917). 

23.  Claus,  J.  prakt.  chem.  (2)  84,  441  (1911);  of.  Knueppel,  Ann. 

310.  75  (1900). 

34.  Michaelis,  Ber.  51  (1887)  ; Ann.  320.  298  (1902) . 

25.  Bertheim,  Ber.  276  (1914) . 

33.  Franzen  and  Engle,  J.  prakt.  chem.  (2)  103,  156  (1921) ;102,  187 

27.  Reverdin  and  Crepieux,  Ber.  33.  2498  (1900). 

28.  Meldola,  Proc.  Chem.  Soc.  ]/7,  133  (1901). 

39.  Benda,  Ber.  44,  3302  (1911);  ^7,  1006,  1313  (1914). 

30.  Pyman  and  Reynolds,  J.  Chem,  Soc.  cf.  1181  (1908). 

31.  Bertheim,  Bar.  539  (1910). 

32.  D.R.P.  193,542.  Frdl.  8,  1339. 

33.  C.W.Rodewald  and  Adams,  unpublished  notes. 

34.  Simon,  Bull.  soc.  Chim.  (3)  476  (1895) 

35.  Kostanecki  and  Kat schalowsky,  Ber.  2347  (1904)  Anm, 

36.  Ingvaldsen  and  Bauman,  J.Biol.  Chem.  145  (1930). 

37.  La  Coste,  Ann.  2^,  9 (1881). 

38.  Quick  and  Adams,  J.  Am.  Chem. Soc.  805  (1933). 


44 

39.  W. Lee  Lewis,  Comsiunioation  reported  at  the  Birmingham 

Meeting  of  the  American  Chemical  Society ,1933. 

40.  Robertson  and  Stieglitz, J, Am. Chem. Soc.  179  (1931). 

41.  Adams  and  Johnson, J. Am. Chem. Soc.  43  3355  (1931). 

43'.  Bauer,  Ber.  48  1579(1915). 

43.  Robertson,  J. Am. Chem. Soc . 183  (1931). 

General  References. 

Bertheim,  ”Handbuch  der  Organischen  Arsenverbindungen" , 1913. 
Morgan,  "Organic  Compounds  of  Arsenic  and  Antimony  ",  1918. 

Meyer  and  Jacobson,  "Lehrbuch  der  Organischen  Chemie% 

Volume  3, part  3 pp.913  - 1014  (1930). 


■r.  rf- 


. . ac  ;' » .liHfivr.  - ' stessraarj;^^---2r;i; 


, r-..;  i , 


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PART  TWO 
BENZYL  AR30NIC  ACID 


"W 


4 


BSNZYL  ARSONIC  ACID 
INTRODUCT ION 

This  work  on  benzyl  arsonic  acid  was  undertaken  with 
the  object  of  obtaining  new  organic  arsenic  compounds  which 
might  prove  of  therapeutic  value.  Although  a large  number  of 
derivatives  of  phenyl  arsonic  acid  have  been  prepared  in  the 
last  fifteen  years,  due  to  the  stimulus  of  Ehrlich  and  Bertheim’ 
work,  there  has  been  little  development  along  the  line  of  ali- 
phatic arsonic  acids.  For  our  work  benzyl  arsonic  acid  seemed 
especially  desirable,  since  it  contained  an  aliphatic  arsonic 
acid  grouping,  -CH3A8O3H2  , and  in  addition  a phenyl  group,  by 
means  of  which  it  was  hoped  to  introduce  certain  other  physio- 
logically active  groupings  into  the  molecule. 

The  only  series  of  aliphatic  arsenic  compounds  which 
has  been  thoroughly  studied  and  applied  in  medicine,  is  the 
methyl  series.  Methyl  arsonic  acid  and  dimethyl  arsinic  acid, 
were  until  recently  the  most  readily  accessible  arsenicals  of 
the  aliphatic  series.  These  two  substances  are  used  thera- 
peutically in  the  form  of  their  salts,  most  commonly,  disodium 
methyl  arsonate  (Arrhenal),  and  solium  cacodylate.  Gautier^ 
recommended  the  use  of  Arrhenal  in  therapeutics  and  stated  that 
it  has  specific  action  on  malaria;  however,  it  does  not  possess 
trypanocidal  properties.  The  latter  fact  is  in  keeping  with 
recent  work  which  has  3ho^vn  that  nitrogen  must  be  present  in 
some  form  in  order  to  produce  specific  trypanocidal  substances. 

Benzyl  arscmic  acid  can  be  very  easily  prepared,  and 
the  problem  was  to  study  the  properties  of  this  substance  with 


46 


the  hope  of  preparing  a derivative  Thich  would  possess  trypano- 
cidal action  and  be  of  low  toxicity*  The  relatively  low  toxicity 
of  the  aliphatic  arsenic  acids  in  general,  makes  them  very  desir- 
able as  starting  materials, 

HISTORICAL  PART 

The  first  work  on  arsenic  compounds  of  the  benzyl 
series  was  reported  by  Michaelis^  and  Paeto^v  in  1885,  From  the 
products  of  the  interaction  of  benzyl  chloride,  arsenic  trichlor- 
ide, and  metallic  sodium  in  dry  ether  suspension,  they  obtained 
dibenzyl arsinic  acid,  tribenzyl  arsine,  and  tribenzylarsine 
oxide.  From  these  substances  a large  number  of  more  complex 
substances  were  obtained,  the  most  important  of  which  were: 

(a)  Tribenzyl  alkyl  arsonium  halides.  These  were  made  by 
heating  tribenzyl  arsine  with  alkyl  iodides  at  100®. 

(b)  Tribenzyl  methyl  arsonium  hydroxide  and  tetrabenzyl 
arsonium  hydroxide^  , These  were  made  from  the  corres- 
ponding iodides  with  silver  oxide;  they  are  very  strong 
bases  and  rapidly  absorb  oarbon  dioxide  from  the  air, 

(c)  Benzyl  arsenious  chloride.  This  was  made  by  heating 
tribenzyl  arsine  with  arsenic  chloride;  it  is  very  un- 
stable and  decomposes  in  the  air: 

C eKsCHsAsCl  2 + 0 C gHsCHsCl  + AsOCl  | 

After  this  work,  no  important  contribution  to  the  | 

4 

benzyl  arsenic  series  was  reported  until  Dehn  and  McGrath  in 
1906  showed  that  the  extension  of  Meyer's  reaction  to  benzyl 
iodide  gave  good  yields  of  benzyl  axsonic  acid.  They  studied 




I i 


47 

the  properties  of  this  acid,  and  found  that  the  arsenic  was  split 
off  frora  the  organic  residue  more  readily  than  in  other  simple 

5 

aliphatic  and  aromatic  ar sonic  acids.  Dehn  obtained  benzyl 
arsine  by  the  reduction  of  benzyl  ar sonic  acid  with  amalgamated 
zinc  dust  and  hydrochloric  acid.  By  the  treatment  of  benzyl 
magnesium  chloride  in  ether  soluticn  with  arsenic  tri oxide, 

Sachs  and  Kantorowicz  obtained  a substance  which  they  formulated 
as  a hydrated  dibenzyl  arsenious  acid,(C6HsCH3)  ^AsOH*  HgO  , but 
the  constitution  of  this  acid  was  not  proved  and  needs  verifica- 
tion. 

7 

In  1915  shortly  before  his  death,  Bertheim  studied 
the  mixed  aromatic-aliphatic  secondary  arsinic  acids,  and  ob- 
tained benzyl  phenyl  arsinic  acid  by  treating  sodium  phenyl 
arsenite  with  benzyl  chloride. 


^VTTJ^i 


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■f>, 


THirOPSTICAL  PART 

Sinoe  considerable  quantities  of  benzyl  arsonic  acid 
would  be  required  for  this  work  it  was  desired  to  find  a conven- 
ient method  of  preparing  the  substance.  The  method  of  Dehn  and 
McGrath  is  too  unwieldy  for  the  preparation  of  large  quantities 
of  the  substance  and  involves  a considerable  loss  of  material 
due  to  a side  reaction; 

CeHsCHgl  + K3ASO3  aicohat  CsHbCH^AsOsK^  + KI 

"5”  60J 

Side  reaction; 

C6H5CH3I  + CgHsOK  C6H5CH3OC2H5  + KI 

By  omitting  the  use  of  alcohol,  and  using  a higher  temperature 
and  vigorous  mechanical  stirring,  benzyl  arsonic  acid  was  pre- 
pared in  good  yields  from  benzyl  chloride  or  bromide,  and  aqueous 
sodium  arsenite. 

Benzyl  arsonic  acid  was  thus  readily  available  at  a 

low  cost,  and  seemed  promising  as  a starting  point  for  a number 

of  derivatives.  By  reduction,  benzyl  arsine  is  obtained,  and  it 

seemed  worth  while  to  study  this  substance  by  trying  to  react  it 

with  aldehydes  to  produce  substances  similar  to  those  obtained 

8 

by  Adams  and  Palmer  ; 

CgHsAsHg  + 3RCH0 CgHsAs 

It  was  found  that  the  reaction  did  not  proceed  as  smoothly  as 
with  phenyl  arsine,  and  the  chief  products  of  the  reaction  were 
benzyl  arsonic  acid  and  a red  condensation  product,  (probably 


CHOH-R 

CHOH-R 


1 


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identical  with  that  obtained  by  Dehn  from  benzyl  arsine),  which 
is  presumably  arseno-phenylmethane,  (CeHsCHgAs^AsCHgCeHs)^. 

Recent  work  in  this  laboratory  has  given  two  new 
methods  by  which  derivatives  of  the  arsines  may  be  prepared,  and 
these  may  prove  to  be  useful  in  the  case  of  benzyl  arsine.  The 
reactions  involved  are: 

(af  CsHsAsHa  — CgHsAsNaa -2-^' CgHgAsRa  + 3NaCl 


10 

(b) 


CeHsAsHa 


R M q B r 


CsH^Ab (MgBr), 


CgHg AsRR ’ 
CgHg AsRg 


It  seems  likely  that  a number  of  interesting  derivatives  could  be 
prepared  from  benzyl  arsine  by  the  application  of  these  new  re- 
actions. 

During  the  course  of  the  work  on  the  preparation  and 
properties  of  benzyl  arsonic  acid  some  interesting  observations 
were  made  on  the  products  of  its  decomposition.  It  was  noted  that 
in  general  the  arsenic  compounds  of  the  benzyl  series  were  very 
easily  broken  down  into  inorganic  derivatives  of  arsenious  acid 
and  organic  benzyl  derivatives.  Michaelis  and  Paetow  observed 
that  on  heating,  dibenzyl  arsinic  acid  was  decomposed  into 
arsenic,  benzaldehyde  and  dibenzyl: 

CeHsCHg 


AsOgH 


heat 


ASg  + 3HgO  + 3C6H5CHO  + (CsHsCHs), 


CeHsCHs 

By  strong  hydrochloric  acid  it  is  decomposed  completely  into 
arsenic  chloride,  benzyl  chloride  and  toluene: 

(CgHsCHs)  AsOgH  + 4HC1 =» CsHsCHgCl+CsHsCHa+AsCla+HgO 
These  reactions  are  somewhat  similar  to  the  decomposition  of 


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dibenzyl  mercury: 


(CsHbCHs)  Hg 


(CsHbCHb)  + Hg 

9 

beat 


acetrc"^  CeHsCHgOAo  + CsHsCHg  + Hg 


Michaelie  and  Paetow  observed  that  the  quaternary  benzyl  arsonium 
hydroxides  on  heating  with  alkalies  gave  tolu5ne  and  a tertiary 
arsine  oxide: 


(CgHgCHg)^  AsOH  (CsHbCHsJj  AaO  + CeHsCHg 

Benzyl  arsenious  chloride  was  also  found  to  be  extremely  easily 
decomposed;  with  water  it  gives  benzaldehyde  and  arsenic  trioxide. 

Dehn  and  McGrath  showed  that  strong  hydrochloric  acid 
decomposed  benzyl  arsonic  acid  into  benzyl  chloride  and  arsenic 
trioxide: 

3 CeHsCHgAsOaHg  + 3HC1 -SCsHsCHgCl  + AsgOa  + 3HgO 

and  Bertheim  states  that  warm  hydrochloric  acid  converts  the 
secondary  arsinio  acid,  benzyl  phenyl  arsinic  acid,  into  benzyl 
chloride  and  phenyl  arsenious  chloride: 

CsHsCHgAs^®^®  ' > CsHsCHgCl  + CsHsAsClg  + 3HgO 
OgH 

It  was  observed  that  the  halogenated  benzyl  arsonic  acids  behaved 
in  the  same  way,  yielding  the  halogenated  benzyl  chlorides  on 
treatment  -with  strong  hydrochloric  acid  with  slight  warming. 

On  heating  sli^tly  above  its  melting  point,  benzyl 
arsonic  acid  is  decomposed  into  arsenic  trioxide  and  a liquid 
product.  The  liquid  was  investigated  by  Dehn  and  McGrath  and 
stated  to  consist  of  benzyl  alcohol,  benzaldehyde,  atilbene  and 
water.  They  give  as  the  most  Important  reaction: 


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51 

3 CgHBCHsAaOsHa CgHsCHsOH  + CsHgCHO  + ASgOa  + SHgO 

It  will  be  noted  on  careful  observation  that  this  equation  does 
not  balance;  the  products  of  the  reaction  have  two  hydrogens  and 
two  oxygens  in  excess  of  the  starting  materials. 

On  carefully  decomposing  a large  quantity  of  benzyl 
arsonic  acid  the  chief  reaction  was  observed  to  be: 

3 CsHsCHsAsOaHs-i^^^  SCsHbGHsOH  + ASgOg  + HgO 
No  benzaldehyde  'me  found  in  the  lirquid  product  obtained  from  two 

hundred  grams  of  benzyl  arsonic  acid,  but  a high  boiling  material  ' 

was  obtained  which  was  shown  to  be  dibenzyl  ether.  This  may  be 

accounted  for  by  the  following  equation: 

3 CeHsCHsAsOaHs^^^  (CsHsCH2)20  + A82O3  + SHgO 
or  possibly  by  a secondary  reaction  whereby  a part  of  the  benzyl 

alcohol  formed  is  dehydrated  under  the  influence  of  unchanged 

benzyl  arsonic  acid  in  the  reaction  mixture.  The  hi^  boiling 

material  obtained  by  Dehn  and  McGrath  was  shown  to  be  dibenzyl 

ether,  and  not  a mixture  of  benzyl  alcohol  and  stilbene  as  they 

considered  it  to  be. 

By  decomposing  benzyl  arsonic  acid  under  vigorous 
heating  it  was  noted  that  benzaldehyde  was  obtained  among  the 
decomposition  products,  along  with  an  ill-smelling  gas.  From 
these  considerations  it  seemed  likely  that  benzaldehyde  is  not 
one  of  the  main  products  of  the  reaction,  but  is  formed  by  a 
side  reaction: 

5 CeHsCHsAsOsHs-^^SGsHBCHO  + AS2O3  •fAsH3  + SHgO 

The  decomposit  ion ‘'ol' fcenzyl  arsonic  acid  by  mineral 
acids,  such  as  hydrochloric  and  sulfuric,  is  quite  complete  at 


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elevated  temperatures,  and  it  was  found  that  this  procedure  could 
he  used  to  determine  benzyl  arsenic  acid  quantitatively.  The  ease 
of  preparing  very  pure  benzyl  ar sonic  acid  has  led  to  the  use  of 
the  latter  as  a standard  for  determining  the  titre  of  iodine  solu- 
tions, and  very  good  results  have  been  obtained. 

In  determining  the  melting  points  of  various  samples 
of  benzyl  arsenic  acid  it  was  observed  that  in  some  cases  the  acid 
seemed  to  melt  near  190°  instead  of  the  recorded  melting  point  of 
167°,  which  was  observed  in  other  samples.  It  was  thought  at 
first  that  this  could  be  explained  by  the  manner  in  which  the 
samples  were  heated,  but  a series  of  experiments  showed  that  this 
would  not  completely  account  for  the  two  melting  points  of  the 
substance.  This  suggested  that  perhaps  the  results  were  due  to 
the  existence  of  tautomers  of  the  type  observed  in  the  phenyl 
nitromethane  series: 

m.p.167^  m.p.l90° 

CeHsCHaAB^^Qg'  Z: ; CsHsCH=A3  (OH)  , 

However,  no  method  could  be  found  for  the  interconversicn  of  the 
"tautomers",  and  it  was  decided  to  prepare  certain  substituted 
benzyl  arsenic  acids. 

Attempts  were  made  to  obtain  m-  and  p-nitrobenzyl 
arsenic  acids  by  the  reaction  of  m-  and  p-nitrobenzyl  chlorides 
with  sodium  arsenite  under  the  same  conditions  used  for  benzyl 
chloride,  but  no  arsonic  acid  could  be  isolated  frari  the  reaction 
mixture.  Similar  negative  results  were  obtained  with  diphenyl 
chlorome thane,  and  1 -phenyl -1 -or omoe thane.  The  halogen ated  benzyl 

halides  reacted  normally  and  the  following  halogen  substituted 


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54 


EXPERIMENTAL  PART 
Benzyl  Araonic  Acid 

Dehn  and  McGrath  obtained  this  substance  by  the 
action  of  benzyl  iodide  on  potassium  arsenite  in  alcoholic  solu- 
tion at  room  temperature,  but  the  great  difficulty  in  handling 
benzyl  iodide  and  the  cost  of  the  reagents  indicated  that  this 
would  not  be  a suitable  method.  After  several  experiments  with 
benzyl  chloride  and  potassium  and  sodium  arsenites  in  boiling 
alcohol,  it  was  found  that  excellent  results  could  be  obtained  by 
the  use  of  benzyl  chloride  and  aqueous  sodium  arsenite  at  100^  to 
130^.  Results  of  this  and  similar  experiments  with  various  other 
halides  are  reported  by  Quick  and  Adams' ^ and  in  general  it  has 
been  found  advantageous  to  omit  the  use  of  alcohol.  The  only  ex- 
ception to  this  is  the  case  of  methyl  arsenic  acid  which  separates 
from  the  alcoholic  reaction  mixture  almost  quantitatively  as  the 
di sodium  salt. 

Preparation:  In  a flask  provided  with  a mechanical  stirrer  and  a 

good  reflux  condenser  was  placed  a solution  of  99  g.  of  arsenic 
trioxide  (i  mole)  and  134  g,  of  sodium  hydroxide  (3  moles)  in 
350  cc.  of  water.  The  solution  was  heated  to  100^  to  110  in  an 
oil  bath  and  during  the  course  of  30  minutes  137  g,  of  benzyl 
chloride  (1  mole)  was  added  by  means  of  a dropping  funnel.  The 
mixture  was  boiled  vigorously  for  1^  to  3 hours  longer  and  then 
cooled  to  room  temperature.  The  oil  which  floated  on  the  surface 
was  extracted  with  a small  q;uantity  of  benzene  and  the  alkaline 
solution  diluted  with  li  to  3 moles  of  water  and  carefully 


5B 


neutralized  to  litmus.  This  must  be  done  by  the  addition  of 
dilute  acid  with  good  stirring  bet’,veen  additions,  or  some  of  the 
benzyl  arsonic  acid  will  be  precipitated.  If  this  procedure  was 
carried  out  properly,  a slight  flocoulent  precipitate  was  obtained  , 
at  this  point.  The  neutral  solution  was  filtered  and  the  precipi- 
tate discarded. 

Dilute  hydrochloric  acid  was  added  to  the  clear  fil- 
trate until  it  reacted  acid  to  Congo  paper,  and  the  benzyl  arsonic 
acid  separated  out  as  a thick  white  curd.  This  was  filtered  with 
suction,  washed  with  water  until  free  from  acid,  and  dried  in 
vacuo  at  90^.  The  yields  were  from  130  to  135  grains,  which  is 
30  to  63*^  of  the  theoretical  amount.  The  oil  v/hich  is  formed  in 
the  reaction  consists  of  benzyl  alcohol  (75f^)  and  dibenzyl  ether 
(25fc)  and  this  accounts  for  30  to  35fo  of  the  original  benzyl 
chloride. 

Benzyl  arsonic  acid  may  be  purified  by  crystallization 
from  water,  95^  alcohol,  or  glacial  acetic  acid.  Alcohol  is  to 
be  preferred  since  the  acid  is  much  more  soluble  in  this  solvent 
at  the  boiling  point,  than  in  hot  water.  From  water,  the  benzyl 
arsonic  acid  crystallized  in  stout  white  needles;  from  alcohol  in 
small  needles  or  plates;  from  glacial  acetic  acid  in  small  needles. 

A sample  was  analysed  by  Fwins*  method: 

Subs.  0,2023  g,  required  25,10  cc.  0,0736  N Iodine; 

Fo^ond:  As  » 34.41*i^;  Calculated  for  C^HgOgAs:  As  • 34. 72fc. 

0 

The  melting  point  given  by  Dehn  and  McOrath  is  167  and  a number 
of  samples  were  obtained  with  this  melting  point,  but  in  certain 
oases  the  melting  point  was  in  the  neighborhood  of  190°  and  a 


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56 


number  of  experiments  were  made  to  determine  the  reason  for  this. 

It  was  definitely  shown  that  the  difference  was  not 
due  to  water  of  crystallization,  since  material  crystallized 
from  alcohol  and  analysed  for  arsenic  showed  similar  behavior. 

It  was  noticed  that  the  rate  of  heating  had  a marked  effect  on  | 
the  melting  point,  but  this  could  not  account  for  all  of  the  dis- 
crepancies, A sample  of  material,  for  example,  that  crystallized 
from  glacial  acetic  acid,  was  heated  slowly  in  the  bath  and 
melted  from  191^-193®;  a sample  of  the  same  material  immersed  at 
170°  and  heated  more  rapidly  melted  at  192°, 

The  two  melting  points  observed  could  be  explained  by 

the  existence  of  the  tautomeric  forms, 

-CHs-As  -CH=As  (OH)  a 

but  in  this  case  no  means  could  be  found  for  passing  from  one 
form  to  the  other  with  certainty,  and  it  was  decided  to  prepare 
substituted  benzyl  arsenic  acids  to  see  if  the  same  double  melt- 
ing point  would  be  observed. 

Disodium  Benzyl  Ar senate:  This  salt  was  prepared  by  adding  two 

moles  of  sodium  ethylate  to  a hot  alcoholic  solution  of  benzyl 
arsonic  acid.  It  separates  in  crystalline  leaflets  which  were 
filtered  with  suction  and  washed  with  dry  ether.  This  salt  dis- 
solves readily  in  water  to  a clear  solution,  ^ich  is  slightly 
alkaline  to  litmus. 

Lead  Benzyl  Arsenate t The  lead  salt  of  benzyl  arsonic  acid  was 
prepared  by  adding  a solution  of  lead  acetate  or  nitrate  to  a 
solution  of  the  mono-sodium  salt  of  benzyl  arsonic  acid,  A 
heavy  curdy  white  precipitate  was  obtained. 


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57 


Decomposition  on  Heating:  Since  the  nature  of  the  products  of 

decomposition  of  benzyl  ar sonic  acid  might  prove  of  value  in 
studying  tne  possible  tautoraerism,  the  following  experiment  was  f 
carried  out : j 

50  g.  of  re cry stall! zed  benzyl  arsonic  acid  was  heated  5 
in  a small  flask  over  a free  flame  until  decomposition  commenced. 
After  the  reaction  was  started,  it  proceeded  without  further  heat- 
ing, although  at  the  end  the  material  was  heated  to  insure  com- 
plete decomposition.  The  product  of  the  reaction  consisted  of 
whits  arseni c trioxide,  and  a clear  oil.  The  weight  of  the  solid 
vsupied  from  34-37  grams,  and  the  liquid  from  13-19  g.  The  latter 

was  washed  out  with  ether  and  fractionally  distilled.  The  main 

0 

product  boiled  from  300-310  ; then  the  thermometer  rose  to  380 

and  a fraction  was  collected  from  380°  to  300°.  The  higher 

fraction  amounted  to  about  10^-  of  the  liquid  product. 

It  was  apparent  that  no  considerable  amount  of  benzal- 
dehyde  was  formed,  since  the  thermometer  rose  immediately  to  the 

boiling  point  of  banzyl  alcohol  and  nothing  passed  over  at  180°, 

From  the  300-310°  fraction  on  redistillation,  a main  fraction  was 

obtained  boiling  from  303°-307°,  which  was  shoTO  to  be  benzyl 

alcohol  by  conversion  into  the  p-nitrobenzoyl  derivative,  ra.p, 

83°.  (33.5°-S4.5°  in  the  literature).  I 

In  order  to  investigate  the  higher  boiling  fraction, 

the  combined  380°-300°  fractions  from  the  deooraposition  of  300  g. 
of  benzyl  arsonic  acid  were  redistilled,  and  a sainple  of  pure 
material  boiling  from  398°-302°  was  collected.  The  latter  was 
purified  by  two  distillations  and  was  then  used  for  the  determin- 


58 


ation  of  physical  constants.  The  analysis  of  the  high  boiling 

material  is  reported  by  Dehn  and  McGrath,  and  checks  satisfactorily 
for  dibenzyl  ether: 


Calculated  for  C14H14O:  C « 84.85^;  H - 7.07fo. 

Found,  (by  Dehn  and  McGrath):  C • 84.65^;  H - 7,95‘fo, 
Physical  Constants:  Decomposition  Product  Dibenzyl  Ether 


Specific  Gravity  1,04 

Refractive  Index  1.5593 

Boiling  Point  298®-303® 


1.036 

1.5597 

295^-298° 


The  above  evidence  proves  that  the  high  boiling  fraction  is  not  a 


mixture  of  benzyl  alcohol  and  stilbene,  but  pure  dibenzyl  ether’ 
Dehn  and  McGrath  state  that  their  product  decolorized  bromine 
water,  but  we  were  unable  to  confirm  this.  A sample  of  high  boil- 
ing material  prepared  according  to  their  procedure  failed  to  de- 
colorize bromine  water,  and  our  sample  of  dibenzyl  ether  did  not 
decolorize  this  reagent. 

In  order  to  see  whether  benzaldehyde  might  be  formed 
under  some  other  circumstances,  a sa^rple  of  benzyl  arsonic  acid 
was  moistened  with  water  and  heated  in  a 200  cc.  flask  over  a free 
flame.  An  ill-smelling  gas  was  formed  dtoring  the  reaction,  and 
the  distillate  consisted  of  water  and  an  oil,  smelling  strongly 

of  benzaldehyde.  The  water  was  separated  from  the  heavier  oil, 
and  the  latter  was  shaken  with  sodium  bisulfite  solution  and 

ether  added  to  take  up  the  insoluble  portion.  The  bisulfite  j 

* In  order  to  show  that  the  dibenzyl  ether  obtained  was 


not  formed  by  a secondary  reaction  from  benzyl  alcohol 
and  arsenic  trioxldc,  7b  g.of  benzyl  alcohol  and  an  equal 


weight  of  areenic  trioxido  were  boiled  together  for  45 
minutes  under  reflux.  The  mixture  after  cooling  and  extract- 
ion with  ether  was  distilled  and  no  dIbenzyl  ether  was 


found  . 


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extract  made  alkaline  with  sodium  oarhonate,  and  steam  dis- 
tilled, when  a clear  white  oil  having  the  odor  of  hen2Ealdehyde 
passed  over.  This  was  extracted  with  ether  and  identified  as  the 
phenyl  hydrazone,  m.p,  154°-155®,  (m.p,  155°-156°,  of  phenyl  hydra- 

zone  from  known  benzaldehyde) , A mixed  melting  point  of  these  two  | 

i 

substances  was  unaltered.  This  proves  conclusively  that  benzalde- 
hyde  can  be  formed  when  benzyl  arsonic  acid  is  decomposed  by  heat, 
but  it  is  not  one  of  the  main  products  of  the  reaction.  The 
following  equation  is  suggested  for  its  formation: 

3 CsHsCHgAsOsHg SCqHsCHO  + AsgOs  + A3H3  + 3HgO 

The  arsine  formed  in  this  reaction  accoiJints  for  the  ill-smelling 

gas  which  is  evolved,  and  its  decomposition  by  heat  would  account 
for  the  deposit  of  metallic  arsenic  observed  in  the  flask  and  con- 
denser tube. 

Deoomoosition  by  Mineral  Acids:  Concentrated  hydrochloric  acid 
decomposes  benzyl  arsonic  acid  in  the  cold  with  the  formation  of 
benzyl  chloride  and  arsenic  chloride.  Strong  sulfurio  acid  decom- 
poses it  in  the  cold  with  the  formation  of  arsenious  acid  and  a 

gummy  material.  If  the  benzyl  arsonic  acid  is  dissolved  in  hot 
water  and  a few  cc.  of  strong  sulfurio  acid  added  and  the  mixture 
'ooiled  for  a short  while,  the  decomposition  is  quantitative,  as 

stated  bv  Dehn  and  McGra,th: 

1000 

CeHBCHjAsOsHj  CsHbCHsOH  + H3ASO3 

sulfuric 

By  using  the  follomng  procedure  it  was  found  that  a simple  quan- 
titative determination  of  benzyl  arsonic  acid  could  be  made.- 
Samples  of  pure  benzyl  arsonic  acid  weighing  0,2  to 
0.4  g.  were  placed  in  a 500  cc.  erlenraeyer  flask,  lOO  cc.  of  water 


added  and  the  acid  dissolved  by  boiling  on  a wire  gauze.  After 
cooling,  10  oc.  of  concentrated  sulfuric  acid  were  added  and  the 
solution  boiled  gently  for  30  - 30  minutes.  It  was  then  cooled, 
neutralized  with  alkali  and  faintly  acidified  with  sulfuric  acid. 
Sodium  bicarbonate  was  then  added  and  the  arsenious  acid  titrated 
with  standard  iodine  in  the  usual  way. 

Weight  of  Sample  Iodine  Solution  Arsenic  Found 


0.4134  g.  52.6  3 cc  34.88  fo 

0.2109  g.  33.54  cc  34.73  fo 

0.1732  g.  21.73  cc  34.33  $ 

0.1874  g.  33.53  cc  34.34 

0.2013  g.  25.33  CC  34.39  ^ 

0.2435  g.  30.58  cc  34.30  i 

Calculated  for  Benzyl  Arsonic  acid 34.72  ‘^o 


Average  of  six  determinations  above  34,73  ^ 

Iodine  solution  * 0,0736  Normal, 

Using  this  method,  the  solubility  of  benzyl  arsonic  acid  in  water 
at  35®  was  found  to  be  0.369  g,  per  100  cc,  of  solution,  Dehn 
and  McGrath  found  0.34  g.  at  23.5®  and  0,39  at  27°.  Interpolation 
of  their  results  for  35®  gives  0.368  g.  per  100  cc,,  which  is  in 
close  agreement  with  the  above  result. 

Benzyl  Arsine 

This  substance  is  described  by  Dehn,  who  obtained  it 
in  the  usual  manner  by  the  reduction  of  the  arsonic  acid  with 
amalgamated  zinc  and  strong  hydrochloric  acid.  In  practice  it 
was  found  advisable  to  mix  the  benzyl  arsenic  acid  with  water,  so 


' r 


^ ► p 


li?i: 


i € 


A 


61 


that  the  acid  used  ivould  not  he  sufficiently  strong  to  decompose  it. 

Preparation:  In  a flask  provided  with  a mechanical  stirrer  and  an 
efficient  hulhed  reflux  condenser  were  placed  100  g.  of  pure  benzyl 

! 

arsonic  acid,  750  g.  of  amalgamated  zinc  dust,  500  co.  of  water  and j 
500  cc.  of  ether.  This  mixture  was  stirred  vigorously  and  concen-  ! 
trated  hydrochloric  acid  was  allowed  to  run  in  slowly  from  a drop- 
ping funnel,  and  ether  was  added  from  time  to  time  to  maintain  the 
original  amount  of  about  500  cc,  After  two  or  tliree  days  the 
ethereal  layer  was  drawn  off  into  a 350  cc,  Claissen  flask  from 
which  it  was  distilled  in  portions.  The  residue  consisted  of 
benzyl  arsine  and  water,  and  was  distilled  under  reduced  pressure 
in  an  atmosphere  of  nitrogen.  Water  first  distills  off  and  then 
the  benzyl  arsine  comes  over  as  a clear  white  liquid,  gradually 

0 

becoming  yellow  on  standing.  The  boiling  points  observed  were  95 
at  30  mm,,  and  90^  at  24  ram.  Dehn  reported  140^  at  360  ram.  The 
yield  was  37-^  g,  which  is  50“;^  of  the  theoretical  amount . 

Reaction  with  Benzaldehyde:  37|-  g,  of  benzyl  arsine  was  mixed 

with  47  g.  of  benzaldehyde  (3  moles)  and  a few  drops  of  strong 
hydrochloric  acid.  The  mixture  became  quite  warm  and  formed  a 
pasty  mass.  The  latter  was  washed  with  dry  ether,  but  only  an 
insoluble  red  product,  benzaldehyde,  and  benzyl  arsonic  acid  could 
be  identified  in  the  mixture.  A repetition  of  the  reaction  gave 
the  same  results. 

Substituted  Benzyl  Arsonic  Acids 
The  instability  of  benzyl  arsonic  acid  toward  mineral 

acids  limits  the  reactions  which  can  be  applied  to  this  substance 


or.  !;  j;.  i r_ir 


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ii 


6S 

a.nd  therefor©  it  was  decided  to  try  certain  substituted  benzyl 
halides  in  Meyer's  reaction,  to  obtain  the  desired  derivatives. 

Experiments  with  ra-nitrobenzyl  chloride,  p-nitrobenzyl 
chloride,  diphenyl  chloromethane,  and  1-phenyl -1-bromoethane  did 
not  lead  to  the  desired  ar sonic  acids,  but  the  halogenated  benzyl 
halides  were  found  to  give  the  corresponding  halogenated  benzyl 
arsonic  acids  in  good  yields, 

4-Chlorobenzyl  Arsonic  Acid 

Preparation:  p-Chlorobenzyl  chloride  was  prepared  by  the  action 

of  chlorine  in  the  s'onlight  on  an  excess  of  pure  p-chlorotoluene, 
heated  to  boiling.  The  product  was  purified  by  distillation  under 
atmospheric  pressure  and  then  in  vacuo.  The  reaction  was  carried 
out  as  described  for  benzyl  arsenic  acid,  except  that  a 30*^  excess 
of  the  sodium  arsenite  was  used.  The  product  separated  out  as  a 
mass  of  fluffy  white  crystals,  in  a yield  of  60  per  cent  of  the 
thebretical  amount.  p-Chlorobenzyl  arsonic  acid  may  be  crystal- 
lized from  water  or  dilute  alcohol;  it  is  quite  soluble  in  hot 
95^  alcohol  and  does  not  separate  on  cooling;  it  is  insoluble  in 
ether  and  organic  solvents,  m.p,  184^. 

Analysis:  (Robertson*  s method) 

Subs.  0.3482,  0.2475  g. ; required  24.52,  34.23  cc  0,0808  N I. 

Calc,  for  C^HgOjClAs:  As  = 29.92fo;  Found:  As  = 29.93fn. 

This  acid  is  decomposed  by  warm  mineral  acids  in  the  same  way  as 
benzyl  arsonic  acid;  with  strong  hydrochloric  acid,  p-chlorobenzyl 
chloride  is  formed. 


63 


2~Clilorobgnzyl  Araonic  Acid 

In  considering  the  preparation  of  the  halogen  substi- 
tuted benzyl  arsonic  acids  it  was  no'ied  that  the  halogenated  benzyl 
bromides  were  more  easily  prepared  than  the  chlorides,  and  since 
the  former  react  equally  well  with  sodium  arsenite,  it  was  decided 
to  use  them.  A great  deal  of  difficulty  is  experienced  in  handling 
these  substances  since  they  are  very  powerful  lachrymators,  and  to 
avoid  this  a simplified  method  was  employed. 

General  Procedure:  One  mole  of  the  pure  halogenated  toluene  was 
heated  to  boiling  in  the  sunlight,  and  slightly  5-ess  than  one  mole 
of  bromine  was  slowly  added  through  a dropping  funnel.  The  reac- 
tion mixture  after  addition  of  all  of  the  bromine  was  allowed  to 
cool,  and  the  product  washed  with  ice  water.  This  sometimes 
caused  the  material  to  solidify.  The  water  was  separated  by  de- 
cantation, and  the  washing  repeated.  The  crude  halogenated  benzyl 
bromide  was  then  treated  with  a solution  of  1,2  moles  of  sodium 
arsenite,  and  boiled  under  reflux  with  good  stirring.  The  heating 
was  continued  for  6 to  8 hours,  and  the  course  of  the  reaction 
followed  by  titration  of  saiKples  of  the  solution  from  time  to 
time.  The  reaction  is  60^  to  75^  complete  after  the  time  mentioned. 

After  cooling,  the  reaction  mixture  was  extracted  with 
benzene  to  remove  the  oily  layer  and  the  alkaline  solution  was 
treated  with  decolorizing  charcoal  and  filtered.  The  clear  fil- 
trate on  acidification  with  20%  sulfuric  acid*  gave  a white  curdy 


Sulfupio  acid  Is  used 

i n 

p r e f 0 r e 

nee 

t o 

hydr  o«  h 1 or 

I c 

acid, since  a trace  of  t 

h « 

latter 

I f 

not 

removed  by 

the  washing, will  cause 

the 

f 0 r m a t 

1 0 n 

of 

laohrymat I 

ng 

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fi'  l'  .??!-  I f" 


V.  f 


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'••'•  •'l'  - * I ■ ''l.•■'■  '•■l" 


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— -TTr.,'..’  X , .-  ':r.-*  -V 

■ - ';  ',  ■ . , 


64 


prscipit?Lte  of  the  halogenated  oensyl  arsonic  acid. 

Preparation:  Pure  o-chlorotoluene  waa  converted  to  o-chlorohenzyl 
bromide  and  reacted  with  sodium  arsenite  according  to  the  general 
directions.  The  reaction  was  60^  complete  after  four  hours,  and 
no  appreciable  decrease  of  iodine  titration  was  observed  after  an 
additional  four  hours  heating.  The  o-chlorobenzyl  arsonic  acid 
separated  out  as  white  crystalline  flakes,  which  may  be  recrystal- 
lized from  water  or  dilute  alcohol.  From  water  it  is  obtained  in 
small  whits  plates,  m,p,  157-158°. 

Subs,  0.3008,  0.1970  g. required  17.98,  17.66  co.0.0892l  N I 
Calc,  for  CvHeOaClAs:  As  = 39.93f^.  Found:  30. 00fo,30. 37fo. 

4-Bromo benzyl  Arsonic  Acid 

Preparation:  Using  p-bromotoluene  as  described  in  the  general 
procedure,  the  reaction  of  the  p-bromobenzyl  bromide  with  sodium 
arsenita  was  observed  to  be  75^  complete  after  eight  hours.  The 
p-bromobenzyl  arsonic  acid  was  obtained  as  beautiful  white  needles 
from  dilute  alcohol;  m.p,  173°-180°. 

Subs,  0,2497,  0,2500  g,  required  19.42,  19.50  cc.  0.0893  M I 
Calc,  for  C-^HgOgBrAs:  As  = 25,42fo.  Found:  25.46^,  25.53fo. 

2-Bromo benzyl  Arsonic  Acid 

Preparation:  Starting  with  o-bromotoluene,  the  general  procedure 
was  followed  and  the  reaction  between  o-bromo benzyl  bromide  and 
sodium  arsenits  was  observed  to  be  66^  complete  after  eight  hours. 
The  acid  was  obtained  in  the  usual  manner,  and  was  purified  by 
recrystal iizat ion  from  dilute  alcohol,  from  which  it  separated  in 


( t i 


66 


SUMMARY 


A convenient  method  was  fcimd  for  the  preparation  of 
large  quantities  of  henzyl  arsenic  acid,  and  an  interesting  ob- 
servation was  made  on  the  melting  point  of  this  substance. 

The  products  of  the  decomposition  of  benzyl  arsenic 
acid  by  heating  were  investigated  and  the  following  equations  were 
found  to  represent  the  reactions  more  accurately  than  any  previous- 
ly suggested: 


3 CsHbCHsAsOsHs SCsHsCHaOH  + AsgOg  + H2O 


3 CgHsCHgAsOsHg ■*-  (CgH5CHg)20  + ASgOs  + 3HgO 


3 CeHsCHsAsOaHa -SCqHsCHO  +As20a  +AsxHa  +3H2O 

Benzyl  arsine  was  condensed  with  benaaldehyde,  but  no 

simple  compound  of  the  type,  R-As(CHOH-R)^  , could  be  isolated 

from  the  reaction  mixture.  Benzyl  arsenic  acid  and  an  insoluble 

red  product  were  formed. 

A simple  method  has  been  devised  for  the  quantitative 
determination  of  arsonic  acids  of  the  benzyl  series,  based  on  their 
decomposition  by  hot  aqueous  sulfuric  acid. 

The  follovtring  halogen  substituted  benzyl  arsonic  acids 
were  prepared:  0-  and  p-chlorobenzyl  arsenic  acid,  and  0-  and  p- 
bromobenzyl  arsonic  acids. 


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67 


BIBLIOGRAPHY 

1.  Frankel,  "Arzneimittel-Synthsse",  5th  Ed,,  19B1  p,699.  j 

2.  Michaelia  and  Paetow,  Ber.18,  41,  (1885);  Annalen  60  (1686).  | 

3.  Mannheim,  Annalen  308  (1905).  Ii 

4.  Dehn  and  MoGrath,  J.  Am.  Ohem.  Soc.  347  (1906).  | 

5.  Dehn,  Am.Chem.J.  113  (1908). 

6.  Sachs  and  Kantorowicz,  Bar,  ^1,  2767  (1908). 

7.  Bert he im,  Ber.  48,  350  (1915). 

8.  Adams  and  Palmer,  J. Am. Ohem. Soc.  2375  (1920). 

, C.S, Palmer,  University  of  Illinois  Thesis,  1921, 

9.  Unpublished  research,  C.S. Palmer. 

10.  J.L.Hall,  University  of  Illinois  Thesis,  1932. 

Cf.  A, J. Quick,  University  of  Illinois  Thesis,  1921,  pp.57,  SO. 

11.  Jones  and  Werner,  J. Am. Chern. Soc.  JD,  1257  (1918). 

13.  Quick  and  Adams,  J.  Am,  Chem.  Soc.  _44,  805  (1922). 

General  References: 

Bertheira,  "Hand’buch  der  Organ! schen  Arsenverbindungsn",  1913. 
Morgan,  "Organic  Compounds  of  Arsenic  and  Antimony",  1918. 


1 


i 


J 


Oi 


68 


Vita 


The  writer  was  bom  in  Chicago,  Illinois,  on 
August  9,  1900.  He  attended  the  Lincoln  School  in  this 
city  from  1903-1913  and  was  graduated  from  the  Lane  Tech- 
nical High  School  in  1916.  He  attended  the  Lane  Junior 
College  during  1916  and  1917  and  entered  the  University  of 
Illinois  in  1917,  He  was  graduated  from  the  latter  institu- 
tion in  1919  with  the  degree  of  Bachelor  of  Science  in  Chem- 
istry, and  received  the  degree  of  Master  of  Science  in  1990. 
The  following  appointments  were  held  in  the  University  of 
Illinois: 

Graduate  Assistant  In  Chemistry,  1919-1920. 

Social  Hygiene  Board  Fellow, 

Carr  Fellow  in  Chemistry, 


1920- 1931. 

1921- 1922. 


